Containment Manual - ISPE PDF

This Document is licensed to
Mr. Bruno Henrique Santiago Lima

Belo Horizonte, Minas Gerais,
ID number: 1037317
Downloaded on: 1/15/19 11:37 AM
ID number: 1037317
For individual use only. © Copyright ISPE D/A/CH Affiliate 2016. All rights reserved.
ID number: 1037317
ID number: 1037317
ISPE D/A/CH COP CON
Containment Manual
Foreword
Containment and containment solutions become more and more important for manufacturing of
pharmaceutical products and their active ingredients. The knowledge therefore is diversified.
In 2010 first ideas occurred for writing this manual in order to describe the state-of-the-art of
containment and to support all interested parties with this manual.
Many GMP document describe the protection of products and thereby the protection of patients, this
manual in contrast focusses on work safety or operators safety.
Acknowledgement
The Containment Manual was compiled by the work group Containment of ISPE Affiliate D/A/CH
and was sponsored by ISPE Affiliate D/A/CH.
The following persons have been significantly involved in the creation of the Manual:
Henryk Badack Vetter Pharma-Fertigung Ravensberg D

Dirk Collins Hermann Waldner GmbH Wangen D
Richard Denk Skan AG Allschwil CH
Jürgen Fleckenstein Basel CH
Andreas Flückiger F. Hoffmann-La Roche AG Basel CH
Uwe Hahmann HET Filter GmbH Altenstadt D
Friederike Hermann Lonza AG Visp CH
Daniela Kovats Excella GmbH Feucht D
Frank Lehmann Skan AG Allschwil CH
Reinhold Maeck Boehringer Ingelheim GmbH Ingelheim D
Michael Maintok Glatt GmbH Binzen D
Martin Pernau Bayer AG Leverkusen D
Markus Rückert Pharma Containment Solutions Edingen D
Andreas Schreiner Novartis Pharma AG Stein CH
Bernhard Steidle R-Pharm Germany GmbH Illertissen D
Karsten Wolka LS-tec GmbH Reinach CH
Jörg Ziska Hüttlin GmbH Schopfheim D
Co-Authors:
Stefan Gries
Benedict Kleine-Koenig
Boehringer Ingelheim GmbH
Robert Bosch GmbH
Ingelheim
Waiblingen
D
D
Johannes Rauschnabel Robert Bosch GmbH Crailsheim D
Gerhard Schilder Hof Sonderanlagenbau GmbH Lohra D
Malte Schuldt Mr. Bruno Henrique Santiago Lima
HS-Luftfilterbau GmbH Kiel D
ID number: 1037317
For individual use only. © Copyright ISPE D/A/CH Affiliate 2016. All rights reserved. 5
ISPE D/A/CH COP CON
Containment Manual

ID number: 1037317
6 For individual use only. © Copyright ISPE D/A/CH Affiliate 2016. All rights reserved.
ISPE D/A/CH COP CON
Containment Manual
Contents
1 Introduction 13
1.1 Background 13
1.2 Purpose and Objectives 13
1.3 Scope and Usage 13
1.4 Structure of the Manual 14
2 Fundamental Considerations 17
2.1 The Term “Containment” 17
2.2 Primary and Secondary Containment 17
2.3 Thresholds and Hazard Categories of Highly Potent Substances 18
2.4 Thresholds for Planning an Equipment 20
2.5 Regulatory and Legal Requirements 21
2.6 Basic Concepts 22
2.6.1 Building Concept 22
2.6.2 Organizational Measures 23
2.6.3 Flow of Personnel 23
2.6.4 Flow of Material 23
3 Risk Assessment 27
3.1 Risks 27
3.2 Risk Management Process 27
3.3 Methods 28
3.4 Risk Assessments in the Manufacture of Highly Potent Substances 29
4 Life-Cycle of Containment Solutions 33

4.1 Conception, Planning 33
4.2 Procurement 33
4.3 Design 33
4.4 Commissioning, FAT, SAT 34
4.5 Production, Use of Equipment 35
4.6 Repair and Maintenance 35
4.7 Cleaning 36
4.8 Decommissioning 37
5 Process Requirements 41
5.1 Pharmaceutical Production 41
5.1.1 Dispensing Area (Assembling, Weighing, Mixing, Dissolving) 41
5.1.1.1 Weighing the Active Pharmaceutical Ingredients 42
5.1.1.2 Inwards and Outwards Transferring 43
5.1.1.3 Transferring the APIs to the Mixing Tank 44
5.1.2
5.1.1.4 Connecting Product Tubes/Pipes
Granulation and Drying
45
46
5.1.2.1 Mixer for Wet Granulation 46
5.1.2.2 Mixer for Spray Granulation 48
5.1.2.3 Fluid-Bed Granulator 49
5.1.3 Comminution
5.1.2.4 Single Pot Mixer Granulator 51
51
5.1.3.1 Milling ID number: 1037317 51
5.1.3.2 Sieving – Sifting 54
5.1.3.3 Examples for the Usage of Milling and Screening Equipment in Containment 57
5.1.4 Downloaded on: 1/15/19 11:37 AM
Tableting, Coating, Blistering 58
5.1.4.1 Tableting 58
5.1.4.2 Coating 63
5.1.4.3 Blister Packaging 65
ISPE D/A/CH COP CON
Containment Manual
5.1.5 Liquid Filling: Aseptic/Non-Aseptic 66

5.1.5.1 Ampoules 66
5.1.5.2 Vials 67
5.1.5.3 Disposable Syringes 67
5.1.6 Capsule Filling 67
5.1.7 Transfer from Equipment to Equipment 69
5.1.8 Lyophilisation 70
5.1.9 Goods Receiving 74
5.2 Production of Active Pharmaceutical Ingredients (APIs) 74
5.2.1 Charging 74
5.2.2 Processing 77
5.2.3 Solid/Liquid Separation 78
5.2.4 Drying 79
5.2.5 Packaging 81
5.2.6 Transfer 83
6 Technical Systems 87
6.1 Primary Containment 87
6.1.1 Isolators 87
6.1.1.1 Ergonomic Study (Mock-Up) 89
6.1.2 Systems with Low-Turbulence Displacement Flow (Laminar Flow Systems) 90
6.1.3 Restricted Access Barrier System (RABS) 91
6.1.4 Rapid Transfer Ports (RTP) 93
6.1.5 Split Butterfly Valve Systems 96
6.1.6 Split Cone Systems 98
6.1.7 Film Connection Systems 99
6.1.8 Sampling, Samplers 101
6.1.9 Pneumatic Conveyor Systems 102
6.1.10 Other Connections 104
6.1.11 Single-Use Technologies 106
6.1.11.1 Disposable Isolators 106
6.1.11.2 Continuous Liner Systems 108
6.1.11.3 Film Closure Systems 108
6.1.12 Local Extraction Ventilation 110
6.1.13 Safety Cabinets 113
6.2 Secondary Containment 116
6.2.1 Workspaces/Ventilation/Airlock Systems 116
6.2.2 Workspace Concept 116
6.2.2.1 Workspace without Airlocks 117
6.2.2.2 Workspace with Common Personnel and Material Airlock 118
6.2.2.3 Workspace with Separate Material and Personnel Airlocks 118
6.2.2.4 Workspace with Separate Material and Personnel Airlocks for Entrances and Exits 119
6.2.2.5 Additional Technology Zones Separate from the Workspace 119
6.2.3 Pressure Cascade Concept 120
6.2.3.1 Workspace with Positive Air Pressure
6.2.3.2 Workspace with Negative Air Pressure
120
121
6.2.3.3 Negative Pressure Corridor 121
6.2.4 Cleanroom Classifications 122
6.2.5 Cleanrooms 122
6.2.6
6.2.7
Personnel Airlocks
Material Airlocks (incl. Pass-throughs, Mouseholes, Gates)
123
124
6.2.8 ID number: 1037317
Decontamination Systems (Cleaning Systems) 125
6.2.9 Ventilation 125
6.2.10 Media 126
6.3 Downloaded on: 1/15/19 11:37 AM
De-Dusting/Filtration Technology 126
6.3.1 Air Filters 126
6.3.1.1 Coarse Dust Filters 129
6.3.1.2 Fine Particulate Air Filters and High-Efficiency Particulate Air Filters 129
ISPE D/A/CH COP CON
Containment Manual
6.3.2 Handling of Air Filters 130

6.3.3 Exposure Measurements at Filter Units 131
6.3.4 Local Aspiration and Central Aspiration 132
6.3.5 Safe Change Filter Systems 133
6.3.5.1 Push-Push Filter Systems 133
6.3.5.2 Bag-In/Bag-Out Change Method (BIBO) 133
7 Occupational Hygiene/ Industrial Hygiene Validation 141

7.1 Basic Principles 141
7.2 Strategy 141
7.3 Validated Sampling Method 141
7.4 Validated Sample Analysis 143
7.4.1 Selectivity and Specificity 144
7.4.2 Linearity 144
7.4.3 Limit of Detection and Limit of Quantification 144
7.4.4 Precision and Accuracy 144
7.4.5 Recovery Rate 145
7.5 Procedure 145
7.6 Evaluation of the Occupational Hygiene Measurement Results 147
8 Cleaning/Waste Treatment 151

8.1 Process Systems 151
8.1.1 Treatment of Production Wastes 151
8.1.2 Treatment of Packaging Wastes 152
8.1.3 Treatment of Filter Wastes 152
8.1.4 Treatment of Cleaning Wastes 152
8.2 Rooms 153
8.3 Airlocks 153
8.3.1 Material Airlocks in Containment Systems 153
8.3.2 Waste Airlocks in Containment Systems 153
8.3.3 Personnel, Material, and Waste Airlocks in Production Rooms and Sections 154
8.4 Cleaning Media 154
8.4.1 Water as a Cleaning Medium 154
8.4.1.1 Background 154
8.4.1.2 Types of Water Used 154
8.4.1.3 Detergents and Cleaning Agents 154
8.4.1.4 Washing Procedures 154
8.4.1.5 Various Cleaning Cycles 155
8.4.2 Disposal of Wastewater 155
8.5 Contaminated Waste 156
8.6 Post-Treatment of Wastes 156
9 Personnel 159
9.1 Training 159
9.2
Exposure Monitoring 160
10 Appendix 163

10.1 List of Abbreviations 163
10.2 Mr. Bruno Henrique Santiago Lima
Literature 167
10.3 Belo Horizonte, Minas Gerais,
List of Figures and Tables 168
ID number: 1037317
ISPE D/A/CH COP CON
Containment Manual

ID number: 1037317
1 Introduction

ID number: 1037317
ID number: 1037317
ISPE D/A/CH COP CON 1 Introduction
Containment Manual
1 Introduction
The manufacture of active pharmaceutical ingredients (API) and all kinds of products harbours risks
for production workers, patients, and the environment. Various containment solutions and other
preventative measures are deployed in order to reduce these risks to the required level.
This Containment Manual describes the essential elements that must be considered in the imple-
mentation of containment technologies and spans the entire lifecycle from the planning, to the
deployment and operation, right through to the decommissioning.
1.1 Background
The term “containment” is a generic one for many different disciplines, concepts, and technologies,
all of which have in common the protection of people and the environment from contamination with
the potentially dangerous substances being handled.
The knowledge base on the topic of containment is widely dispersed. One of the objectives of this
manual is to summarize and portray the methodologies, processes, and technologies commonly in
use today.
The planning, construction, commissioning, operation, and validation of containment facilities pose
a great challenge for producers, engineers, operators, and suppliers. There is a great number of
regulations, laws, decrees, HSE and GMP rules and directives that must be observed. Different
interpretations of what containment actually means may have led to increased costs for containment
installations in the past.
1.2 Purpose and Objectives

This manual has been developed through the collaboration of experts from various disciplines and
geographic regions working within the ISPE D/A/CH Community of Practice (COP) Containment.
The intention has been to achieve a common understanding and interpretation of requirements on
containment technologies. The manual aims to support the involved functions so they may better
meet customer needs, reduce the production costs, and improve the quality of the product in the
interest of the customer.
1.3 Scope and Usage

This manual can be used by the industry for the planning, construction, commissioning, operation,
and validation of new containment units, as well as for the integration of existing units. The Contain-
ment Manual is neither a technical standard nor a regulation. It is not intended to replace existing
legislation or regulation that apply to facilities of this type. The use of this manual is not only
intended for new facilities or the renovation of existing facilities, but also for the operators of existing
containment facilities, in order to assess the correspondence to the current state-of-the-art.
ID number: 1037317
The manual covers pharmaceutical installations for the production of solid, semi-solid, and liquid
dosage forms, sterile or non-sterile, and also for installations used for the production of active
pharmaceutical ingredients (API). Installations for the production of clinical samples and laboratory
buildings are also included.
1 Introduction ISPE D/A/CH COP CON
Containment Manual
Reference is made to the relevant European and non-European standards in the appendix. Where
applicable, reference is also made to existing ISPE Baseline Guides, e. g.:
▪▪ ISPE Baseline Guide Volume 1 – Active Pharmaceutical Ingredients [1],
▪▪ ISPE Baseline Guide Volume 2 – Oral Solid Dosage Forms [2],
▪▪ ISPE Baseline Guide Volume 7 – Risk-Based Manufacture of Pharmaceutical Products „Risk

MaPP“ [3],
▪▪ ISPE Good Practice Guide – Assessing the Particulate Containment Performance of Pharmaceu-

tical Equipment [4].
This manual does not cover explanations on personal protective equipment, explosion protection,
or bio-safety. The requirements for these topics are to be taken from the appropriate regulations
and guiding documents.
1.4 Structure of the Manual

The manual is divided into the following topics: Risk Assessments, Containment Lifecycle, Process
Requirements, Technical Systems, Validation, Cleaning, and Personnel. Each chapter of the manual
begins with a definition or introduction. Concepts, processes, and technologies are identified and
described in the form of best practices often supported by illustrated examples.

ID number: 1037317
2 Fundamental
Considerations

ID number: 1037317
ID number: 1037317
ISPE D/A/CH COP CON 2 Fundamental Considerations
Containment Manual
2 Fundamental Considerations
2.1 The Term “Containment”

The term “containment” in our context stands for the limitation of the spreading of a substance or
an agent.
“Containment” comprises all measures that limit the spread of highly potent substances, thus also
including very simple ones. Containment is always relative i. e. it does not always refer to a “closed”
system. In practice, normally the question is not “Is containment necessary?”, but “How much
containment is necessary?”
Containment should reduce the spread of an atmosphere which has been more or less contami-
nated with a particular substance within a production environment. The needed level of containment
will depend on the degree of the biological activity of the contaminating substance. The biological
effect is defined by the pharmacological and toxicological potency of the product and the dose that
a person would receive. Processes in which high potent substances are handled will require more
sophisticated containment.
There is no such thing as a completely closed unit. The continuous improvements in analytical
measurement procedures make it possible to detect substances in ever smaller amounts; traces
may be detected even outside of units for which extremely high containment efforts have been
made. One of the drivers for these analytical refinements is that new medicines are becoming
increasingly target-specific within the organism, and are thus more and more potent in ever smaller
doses. They are not only highly potent for the patient, but also for the operator of the equipment who
may be exposed to them – and small residues may become critical in a unit in which other products
may also be manufactured (multi-purpose facility).
In planning containment for an equipment, the complete flow of both personnel and material must
be considered. Protective measures must be planned not only for the production processes, but
also for peripheral and sub-processes. For example, such sub-processes are the maintenance and
repair of exhaust air filter installations in a production line, or the disposal of cleaning equipment for
cleanroom or isolators.
2.2 Primary and Secondary Containment

Primary containment refers to those measures that reduce the spread of a substance from the
actual production equipment. Secondary containment refers to the measures that reduce the spread
of the substance that escaped beyond the primary containment.
Examples of primary containment measures are:
▪▪ Housings for tablet presses and the attached devices such as metal detectors, IPC samplers,
de-dusting units,
▪▪ Isolators used for weighing APIs,
ID number: 1037317
▪▪ Continuous liner systems, e. g. for discharging dryers,

▪▪ Local exhaust systems.
2 Fundamental Considerations ISPE D/A/CH COP CON
Containment Manual
Examples for secondary containment are:
▪▪ Cleanrooms,
▪▪ Airlock systems and pressure gradients between the corridors and the production room,
▪▪ Adhesive floor mats to reduce inadvertent transfer of material via footwear.
When planning the installation, it is important that the primary and secondary containments are
aligned. If the primary containment is good, it may be possible to achieve savings in the secondary
containment. The focus should always be on the optimization of the primary containment.
Recognition of this principle determines the planning of the installation. An installation should be
planned from the inside to the outside. First the equipment should be selected which has a contain-
ment that is suitable for the intended range of products and following that, it should be determined
how the secondary containment needs to be designed.
In turn, based on the production rooms with their secondary containment, the layout of the facility,
the space requirements for it, and then the structure of the building can be elaborated.
These fundamental principles of equipment planning are sometimes difficult to realize, in particular
when an equipment has to be installed in an already existing building structure and limitations exist
for the design layout, e. g. for reasons of building statics.
2.3 Thresholds and Hazard Categories of Highly Potent Substances

As described in section 2.1, the degree of containment required in an equipment can be derived
from the pharmacological/toxicological potency of the substances that are handled.
For decades now, occupational toxicology in the pharmaceutical industry has been dealing with
substance evaluation to answer precisely this question. The result of these occupational toxicological
evaluations are occupational exposure limits (OELs). These OELs are used when defining the
necessary degree of containment for a process.
In this manual, the official German term “Arbeitsplatz-Grenzwerte” (AGW in short, “workplace
thresholds” in English) will be used exclusively for thresholds that are published in the TRGS 900.
If workplace thresholds in general are meant (e. g. those from other official threshold lists or those
set by the pharmaceutical industry itself), then the generic term “Occupational Exposure Limit”
(OEL) is used.
The derivation of an OEL is made in several steps:

1. Purely qualitative determination of the so-called critical effect of the substance.
(What is the first effect on a person when exposed to slowly increasing doses of the substance?)
The critical effect can e. g. be a reduction of blood pressure or the triggering of genetic damage.
For many APIs, the therapeutic effect of a medication is equivalent to the critical effect. In the
case of sensitizing, carcinogenic, mutagenic, or teratogenic substances, this undesirable effect
may already occur at doses where a therapeutic effect has not yet been reached. In such cases,
ID number: 1037317
these undesirable toxic effects are thus the critical effect.
2. The next step is to determine the daily dose at which the critical effect is not quite reached.
The No-Observable-Effect-Level (NOEL) is determined for the target group for whom the OEL
should apply: healthy workers at the workplace. This results in the maximum Acceptable Daily
[Worker] Exposure (ADE). If there is a difference in the sensitivity between female and male,
Containment Manual
then the ADE is set such that the more sensitive gender is not endangered by exposures up to
this ADE. In fact, thresholds must be set such that, in adhering to them, pregnant women and
their unborn children are also protected. According to the definition, the OEL must be based on
a chronic exposure, i.e. eight hours per day, five days per week, for an entire working life.
The NOEL for a worker can almost never be taken directly from the literature; it has to be derived
from the available secondary information. The most important bases for this in the pharmaceu-
tical industry are:
• clinical data from the use of the medicine on humans,
• preclinical data e. g. data from tests on animals.
The best available data set is selected as the starting point for the calculation, so preferably
human data. If this is not available or not sufficiently meaningful, then data should be taken from
long-term studies on animals, preferably with an animal that is representative for humans. The
dosage level selected from these studies is the highest one that still showed no observable
effects, the NOEL of these studies.
If needed a correction can be made according to the following formula if necessary:
NOEL (µg/day)
ADE (µg/day) = .
F1 ⋅ F2 ⋅ F3 ⋅ F4 ⋅ F5
Note that the NOEL is set for a bodyweight of 50 kg (Europe, EMA) or 60 kg (US, FDA).
Note also that correction/adjustment factors are applied as follows:
• F1 when data need to be extrapolated from animals to humans.
• F 2 where additionally the different sensitivities of the human sub-populations need to be

considered.
• F 3 where the duration of the studies is too short (not representative for a lifelong exposure).
• F4 when the substance can trigger very severe effects such as cancer, malformations, or
irreparable damage to organs.
• F5 when the starting point of the calculation was not a NOEL, but certain undesirable effects
were still observed at the lowest tested dose.
3. The ADE measured as μg/day is converted to a respiratory threshold limit value OEL measured
as μg/m3 substance in the breathable air at the workplace.

OELs are always defined as respiratory thresholds, because overall inhalation of contaminated
breathable air is the most important route for absorption of harmful substances at the workplace.
According to international conventions, it is generally accepted that a person breathes about
10 m³ of air in an eight-hour working day:
ADE (µg/day)
OEL (µg/m ) = Belo Horizonte,
3
. 3
Minas Gerais,
10 (m /day)
ID number: 1037317
Example: If the ADE is 100 μg/day, this results in an OEL of 10 μg/m3.

In order to calculate the respiratory threshold limit value from the acceptable daily dose, data
should be considered, if available, that can express how well the substance is absorbed through
the respiratory tract. Taking for instance the substance from the example above, if it is known
Containment Manual
that only 1 % is taken up by breathing, then this results in an OEL of 1000 μg/m3 (100 times
higher than in case the substance was fully absorbed).
It is relatively rare that data are available for absorption through breathing; the so-called “inhala-
tive bioavailability”. In the case of molecules with a molecular weight > 50 kDA, the inhalative
bioavailability is assumed to be 5 %. In the absence of such data, it is assumed by default that
all of the substance that has been breathed in is actually absorbed by the body.
Several other OELs also exist in official lists and still others from recognized expert groups, such as
TLVs (ACGIH, USA), MAKs (DFG, Germany/Suva, Switzerland), AGWs (AGS, TRGS 900,
Germany), VME (INRS, France), PELs (OSHA, USA), but these are not discussed any further here.
If there are insufficient data available for a substance in order to assign a precise OEL, then it is
attempted to assign a health hazard category, ranging from low potency to high potency to the
substance by means of categorization systems. These categories are also referred to as classes or
bands. In English there are numerous terms in common usage, including for example Health Hazard
Categories (HHC) and occupational exposure bands (OEB). These categorization systems are not
harmonized and mostly comprise 4 to 6 categories, whereby the least potent substances are
assigned to category one and those with the highest potency are assigned the highest category
number.
Category OEL Effect
G4 < 1 μg/m3 very high pharmacologic and toxic effect
G 3b < 10 μg/m3 high pharmacologic and toxic effect
G 3a < 100 μg/m3 medium pharmacologic and toxic effect
G2 < 1 000 μg/m3 low pharmacologic and toxic effect
G1 ≥ 1 000 μg/m3 very low pharmacologic and toxic effect
Fig. 1 Example for a classification system
2.4 Thresholds for Planning an Equipment

As a rule, OELs are defined as eight-hour time weighted averages (8-hr TWA). There are also
substances, such as irritants for example, that require short-term limits to be set. E. g. Short-Term
Exposure Limits (STEL) or Short-Term Time Weighted Average (STTWA).
If a substance has an OEL of 100 μg/m3 for example, then it is permissible for a person to be
exposed to concentrations higher than 100 μg/m3 for a limited period of time. The prerequisite for
this is that these periods of higher exposure are compensated for in the same shift by periods of
lower exposure, such that an eight-hour average value of 100 μg/m3 is not exceeded. Attention must
of course be paid to ensure that the height of any exposure spikes are such that they do not cause
any non-desirable effects to health, such as irritations for example.

Where there is a danger of effects due to exposure spikes, short-term exposure limits (STELs) are
defined, often with a reference period of 15 minutes instead of the 8 hours usually used for OELs.
ID number:
In principle, it is often considered as acceptable1037317
that a person can work for 4 hours in the proximity
of a particular piece of equipment/unit where the OEL is exceeded by a factor of 2, if this person
carries out activities for the rest of the shift where he is not exposed to the same substance or other
substances with a similar effect. This requires organizational measures and leads to limited flexi-
bility of personnel. Moreover, practice shows that the absolute necessity of such organizational
measures will not always be taken into consideration or they are sometimes forgotten. This then
Containment Manual
may lead to the risk of overexposure resulting from the accumulated doses from the various activi-
ties that the person has carried out during his shift.
Modern facilities, in particular multipurpose facilities, are planned such that they can operate without
the need for organizational measures, and personnel can be employed in an entirely flexible
manner. To ensure that it is not possible – or at least very improbable – to exceed the OEL during
normal operations, most companies have defined so-called design exposure limits (DEL). DELs are
also referred to as Containment Performance Targets (CPT).
The DEL is not identical with the OEL, but is derived from the OEL of the “most potent” substance
or product, which is to be produced with a particular equipment. The DEL is lower than the OEL, or
has a shorter period of reference than the eight hours of the OEL.
An example of a DEL system:
▪▪ DEL period of reference: The duration of the unit operation (e. g. 8 hours for a packing machine,
10 minutes for a powder transfer process).
▪▪ Differentiation between short and long unit operations:
• long: duration more than 2 hours,
• short: duration less than 2 hours.
▪▪ DEL for long unit operations: 50 % of the OEL (average over the duration of the unit operation;
often less than 8 hours, but can be up to 8 hours).
▪▪ DEL for short unit operations: 100 % of the OEL (average over the duration of the unit operation,
not over 8-hours!).
2.5 Regulatory and Legal Requirements

In the EU, the basic requirements for health protection at the workplace are defined in the Frame-
work Directive 89/391/EEC. This specifies that the employer is obliged to protect the employee
against safety and health risks; the appropriate risk assessments must be carried out and docu-
mented.
Furthermore, the law states that the employees must be protected primarily by technical measures
(also referred to as “collective protective measures”), and that personal protective equipment (PPE)
may only be used as a primary protection against overexposure if technical measures do not exist.
As a matter of principle, the risk posed by hazardous materials at the workplace can be described
by the following formula:
Risk = Hazard ∙ Exposure.

This means that the risk can only be defined if details for the factors “hazard” (in our case the
toxicological pharmacological properties of the hazardous material), and “exposure” (in our case the
level of exposure to these hazardous materials) are available.
ID number: 1037317
Based on the hazard assessment, it is possible to derive the maximum exposure to a hazardous
substance expressed by the OEL or the OEB. If a substance is “only” categorized “banded” without
having its own OEL, then as a rule the conservative “high-tox” end of the category is taken as the
de facto limit, and thus as the containment requirement. The measures applied at the workplace to
limit the exposure must be of a technical nature as far as possible.
Containment Manual
The EU guidelines have been transposed into national law by the member states and this is binding
for companies that are active in the territories of these states. Although slightly diverging formula-
tions resulted, the central statement does remain the same overall. Similar laws also exist in Swit-
zerland, the USA, Canada, in significant countries in Latin America, and in some Asian countries.
Because it is a representation of good work hygiene regulations, the ILO has also taken up these
standards in their recommendations and guidelines (e. g. ILO: Guidelines on occupational safety
and health management systems, 2001), which have in turn been ratified by numerous countries
that do not expressly have such statutory provisions in their regulations. In addition, the same rules
may be found in all relevant textbooks on health protection at the workplace.
GMP requirements stipulate that products must be protected against cross-contamination with other
products. This protective goal is all the easier to achieve, the less substance escapes from the
equipment i.e. the more effective the containment is.
2.6 Basic Concepts
2.6.1 Building Concept

Independently of whether one is dealing with a new building or an existing building, there should be
a concept in which all the regulatory requirements (GMP, HSE, etc.) are described. In this chapter
we will not go into more details concerning building regulations, regulations for the prevention of fire
and explosion, earthquake protection or similar. Essentially, the requirements are described from
the hygiene point of view.
Special building concepts are required when certain substance classes are not permitted to be
manufactured in the same facilities as other substances, and when they must be kept apart from
one another. This is not only valid for production rooms and the corresponding airlocks, but also for
the various media such as liquids and gases and ventilation systems used.
Substance classes which may not be produced in the same facilities used for the production of
other APIs include:
▪▪ Highly potent allergens such as beta-lactams e. g. penicillins or cephalosporins,
▪▪ Radiopharmaceuticals,
▪▪ Live vaccines,
▪▪ Ectoparasiticides (e. g. substances for the treatment of lice).
For all other products, a risk analysis must be carried out to show whether a multipurpose operation
of the facilities concerned is permissible and that the building concept can fulfil all requirements.
Chapters 3 “Premises and Equipment” and 5 “Production” of the EU GMP Good Manufacturing
Practice Guidelines published on August 13, 2014 describe in detail how this should be interpreted.
According to chapter 3, multipurpose operation of facilities is not permitted if
▪▪ the risk cannot be adequately controlled by operational or technical measures (e. g. sufficient
ID number: 1037317
cleaning is not possible),
▪▪ a controllable risk cannot be defined based on the scientific data from the toxicological assess-
ment e. g. sensitizing potential of highly sensitizing substances such as beta-lactams (i.e. it is not
possible to define a scientifically well-founded threshold),
Containment Manual
▪▪ the relevant residue thresholds determined from the toxicological assessment cannot be detected
by validated analytical methods (i.e. there is no analytical method sensitive enough to show that
cleaning has been sufficient).
When considering the cleaning of equipment, the permissible residues must be calculated in
accordance with scientific and toxicological criteria for each substance individually. This is done
following the same principles that are used for calculating the OELs (see chapter 2.3 paragraph 2).
It must be taken into consideration that the route of administration of a substance to a patient
receiving medication containing traces of that substance from a previous production run is not
necessarily by inhalation, but could rather be oral or parenteral. The relevant route of administration
must be considered when setting the threshold, i.e. the ADE for the oral route may be different
(higher) than for the parenteral route. This can be the case e. g. if a substance is not completely
taken up via the oral route i.e. if it has incomplete oral bioavailability.
Once the decision has been made which substances or products are to be manufactured in which
areas and which containment requirements results from the various substance data, the planning
for the actual production areas may begin. This planning should always follow an inside-out
approach. This means that first the equipment should be selected, and the layout of the production
room, the airlocks, the passages, etc. follow from this. Finally, the building envelope is planned.
The operating rooms must be suitable for the intended manufacture/production in terms of number,
type of usage, size, equipment, etc., and designed such that any kind of adverse effect towards
product quality can be avoided (§5 AMWHV, chapter E1).
The operating rooms must be depicted in a true-to-scale site plan.
2.6.2 Organizational Measures

Labor law in some countries stipulates that technical measures are to have precedence over
organizational measures, even if the former may be more costly in terms of effort and investment.
Technical measures are considered to be more reliable than organizational measures.
Organizational measures may be important, however, in order to support the efficacy of technical
protective measures. Typical examples of this are the limitation of exposure periods by shift rotation
from one workplace to another, repair and maintenance plans, standard operating procedures
(SOPs), and signs indicating mandatory or forbidden behaviour.
All organizational measures must be trained repeatedly and training sessions must be documented.
2.6.3 Flow of Personnel

The flow of personnel must be clearly regulated. This can be documented in various plans such as
the layout plan, the site plan, the building plan, or the floor plans (see also chapter 2.6.4).
Depending on the classification, cleanrooms must be accessed via appropriate airlock systems with
a controlled separation of zones. Putting on personal protective equipment and removing it again
takes place in the airlock, as does the decontamination and storage. Short paths should be aimed
for. Passage rooms are not permitted in cleanrooms. Detailed information on technical design is
described in chapter 6.2.
ID number: 1037317
2.6.4 Flow of Material
The flow of material can be described as the chain of the processes Transportation, Provisioning,
Processing or Manufacturing, Testing, and Storage [VDI Guideline 3633], or also the sequence of
the individual process steps from the raw material to the finished product. Depending on the spatial
Containment Manual
arrangement, it is possible to differentiate between the horizontal and vertical flow of material, and
even a mixture of both.
The flow of material must be clearly regulated and depicted in appropriate material flow plans which
permit change tracking (see also section 6.2).
The introduction and removal of materials should be carried out via appropriate material airlocks.
Externally soiled containers must be cleaned in the airlocks in order to avoid contamination with
other materials, and also to prevent unprotected workers coming into contact with the substance.

ID number: 1037317
3 Risk Assessment

ID number: 1037317
ID number: 1037317
ISPE D/A/CH COP CON 3 Risk Assessment
Containment Manual
3 Risk Assessment

Risk assessments are a fundamental component of every hazard management system and the
procedure used, at least initially, is largely independent of the specific topic. People make decisions
every day that are based on risk assessments, often without being conscious of them. It is important
to be aware that there is no such thing as “no-risk”! The challenge lies in being able to determine
or define the “acceptable risk” for oneself, for a given system comprised of hazard and probability
of occurrence.
Depending on just what risks should be evaluated, it is possible to differentiate, for example,
between quality risk assessments (as carried out in ICH Q9), process risk assessments, or health
risk assessments. In all cases an attempt should be made to take all possible hazards into account
within a particular topic, in order to determine the risk that results from this.
3.1 Risks
Risk is generally understood as the probability of the occurrence of an event with negative effects
based on an existing hazard; expressed as a formula:
Risk = Hazard ∙ Probability/Likelihood of Occurrence.
The hazard, i. e. the potential of a certain chemical to cause burns, poisoning, or pharmacological
effects, is given and not modifiable!
The only component that can be influenced is the probability/likelihood of occurrence, or when
considering hazards from contamination by APIs, the duration and degree of exposure.
Examples of risks are:
▪▪ Health Risks for People and the Environment:

The risk assessment is typically responsibility of Occupational Hygiene, Toxicology, and Medicine.
▪▪ Quality Risk:
The risk assessment is typically the responsibility of Quality Assurance.
▪▪ Process Risk:
The risk assessment is typically the responsibility of Engineering Technology, Production, and
Work Safety.
Data processed includes historical data, theoretical analyses and other relevant information, but
also concerns from all involved functions.
3.2 Risk Management Process
The FDA has chosenBelo Horizonte,
the Risk-Based Approach asMinas
its guideline.Gerais,
This considers a) the optimization
of resources i. e. focus is placed on the processes defined as critical, and b) the systematic and
consistent implementation of a ID number:
risk management 1037317
system with risk analysis as its central element.
3 Risk Assessment ISPE D/A/CH COP CON
Containment Manual
Initiation
Risk Management Process
Risk Assessment
Risk Identification
Risk Analysis
not acceptable
Risk Evaluation
Risik Management Tools

Risk Communication
Risk Control
Risk Reduction
Risk Acceptance
Result of
Risk Management Process
Risk Review
Fig. 2 Risk Management Process (depic-
Risk Review Events tion based on ISPE Baseline Guide Risk
MaPP)
The focus of the drug authorities is on the protection of the patient, and thus only indirectly on the
protection of personnel involved in the manufacture. The approach can, however, be used for any
other process.
Firstly, the possible risks (see section 3.1) are determined during the Risk Identification step.
The next step is the Risk Analysis, which examines the causes and consequences of the identified
risks more closely, e. g. using the methods described in section 3.3. Once this has been done, the
Risk Evaluation follows. In this, the factors probability of occurrence and degree of severity of the
identified risk evaluated, i. e. a) how likely it is that an error occurs and remains undetected until
damage is caused, and b) if damage does arise, how big/high is it?
Next, measures are defined to minimize the risk and evaluate whether the possibly remaining risk
is acceptable or not.
The process is rounded off by the review of events that could potentially lead to a new risk assess-
ment.
3.3 Methods This Document is licensed to

There are numerous methods available from both practice and literature that can be used to carry
out risk assessments. The most well-known and accepted methods are:
▪▪ Failure Mode
Belo
EffectsHorizonte, Minas
Analysis (FMEA) (Fig. 3): Gerais,
The breaking down of larger complex processes into smaller manageable steps.
ID number: 1037317
ISPE D/A/CH COP CON 3 Risk Assessment
Containment Manual
▪▪ Failure Mode, Effects and Criticality Analysis (FMECA):

FMEA and links severity, probability and detectability to criticality.
Likelihood of Occurrence
Severity
Risk Priority Number = Likelihood of Occurrence x

Detectability x Severity Fig. 3 FMEA
In practice, risk priority numbers are determined using FMEA and FMECA in order to carry out
the assessment. If the value 5 is set for every factor, then the priority number 125 represents the
highest possible risk.
▪▪ Fault Tree Analysis (FTA):

FTA combines error types with logical operations.
▪▪ Hazard Analysis and Critical Control Points (HACCP):

Systematic, proactive, and preventative approach based on the criticality.
▪▪ Hazard Operability Analysis (HAZOP):

Brainstorming technique.
▪▪ Preliminary Hazard Analysis (PHA):

Method which examines under which conditions a risk occurs.
It is not intended to provide a detailed description with advantages and disadvantages of the indi-
vidual methods at this point.
3.4 Risk Assessments in the Manufacture

of Highly Potent Substances
Here the main focus for protection, next to the product, are the employees and the environment.
Generally, the level of protection is prescribed by the workplace limit specific for each API. These
so-called OELs (Occupational Exposure Limits) specify the maximum permissible averaged amount
of substance that may be present in one cubic metre of air at the workplace during an eight-hour
period. These thresholds are given in µg/m3, for gases and vapors in ppm (parts per million).
IDfor number:
Factors to be considered include example: 1037317
▪▪ the type and duration of the release of the product,
▪▪ the nature of the products, such as pharmacological potency or toxicity, physical characteristics,
▪▪ the flow of materials and personnel,
3 Risk Assessment ISPE D/A/CH COP CON
Containment Manual
▪▪ release of the product during cleaning, maintenance, faults,
▪▪ human activities during the manufacturing process,
▪▪ equipment design and vicinity,
▪▪ safety factors, thresholds,
▪▪ product and operator protection.
In the end, it must be evaluated whether all planned measures to minimize the risk are sufficient or
acceptable, or whether improvements must be made to the concept (action plan). As a matter of
principle, a risk analysis may be carried out at any time. It should, however, already be part of the
planning phase. Special attention should be paid to the team setup for carrying out the risk assess-
ment (expertise, availability, etc.), as risk assessments can be very extensive and significantly affect
the scope of a project.

ID number: 1037317
4 Life-Cycle of
Containment Solutions

ID number: 1037317
ID number: 1037317
ISPE D/A/CH COP CON 4 Life-Cycle of Containment Solutions
Containment Manual
4 Life-Cycle of Containment

Solutions
4.1 Conception, Planning

When planning a production unit for the manufacture of highly potent substances,
the entire life-cycle of the installation must be considered. The basis for the
planning is the User Requirement Specification (URS) or appropriate detailed
specifications. The URS should contain all the information necessary for the
planning with regard to the products and processes, GxP and HSE require-
ments, and if required, the expected life-cycle costs.
A comparison and confirmation of the URS should be carried out by the supplier.
4.2 Procurement
The selection of suitable equipment is of fundamental importance for the safe
manufacture of highly potent or highly hazardous substances.
Besides the technical design, functionality, and the thresholds to be met by the
containment, particular attention should also be paid to the hygienic design of
the containment. In particular, the hygienic design at critical points such as
seals, feed shafts (such as, for example, screw conveyor shafts), connectors,
and interfaces to other systems, plays a decisive role for optimum cleanability,
repair and maintenance, as well as ensuring that the containment is effective.
A supplier should be qualified and/or certified and have a quality management

system in place. If it is not possible to evaluate a suitable supplier oneself, then
this can be done with the support of an external expert.
As containment systems can be susceptible to repairs and maintenance-inten-

sive, the after sales service is also important. Critical replacement parts and
wearparts should be considered as part of the procurement process.
4.3 Design

The design and construction of the surfaces that come into contact with the
product are of special importance for the containment. The hygienic design of
surfaces, borders, flanges, tri-clamp connections, screw conveyor shafts, and
other surfaces the come into contact with the product a significant in determining
the cleanability of an equipment and the ability to fully remove product residues.
Isolators are an example for containments that find frequent use, and especially
in such cases attention must beID
paidnumber:
to ensure that the1037317
glove ports, the integra-
tion of the filters, and the seal of the glass front are perfectly implemented.
Deposits of product dusts at the seals, in connecting pipelines and in shaft seals
must be avoided. Downloaded on: 1/15/19 11:37 AM
In addition to the surfaces that come into contact with the product, the ergo-
nomic design of the equipment must be such that the operator can carry out the
4 Life-Cycle of Containment Solutions ISPE D/A/CH COP CON
Containment Manual
intended activities without constraints. In order to achieve this, feasibility studies

are generally carried out in the form of a so-called mock-up. In the mock-up, the
size and the design of the isolator are simulated by a wooden and/or steel bar
construction. In this system the gloves can still be variably adjusted. Then all the
work activities that are intended to be carried out in the isolator are simulated
and the design is optimized. Operators of different size and gender should be
selected for carrying out the mock-up.
Another possibility is to carry out a computer simulated mock-up.
Besides the design of the equipment, the selection of the materials and surface
quality of the materials used are of importance, especially with regard to solvent
resistance. This is equally valid for stainless steels, plastics, elastomers, and
other synthetic materials. Materials such as, for example, PTFE and Kalrez® are
admittedly very resistant against most solvents, but as they are not elastic, they
can only find limited use as seals in tri-clamp connections or for the isolation of
weighing scales. The topics of conductivity in ex-zones and approval for use in
pharmaceutical operations must also be considered. Many materials are only
partially suitable for use in pharmaceutical production.
The higher the containment, the higher the quality of the surfaces should be. In
many cases, a surface roughness/quality Ra < 0.8 µm is recommended for
surfaces that come into contact with the product. Higher surface qualities can be
attained by electropolishing “if the surface has been prepared for it”. Many
solids, however, do have a tendency to adhere to surfaces, especially to elec-
tropolished ones.
4.4 Commissioning, FAT, SAT

Before commencing operations, the supplier should carry out an FAT “Factory
Acceptance Test”. During the FAT, all critical functions should be tested in detail.
In case a test protocol in accordance with SMEPAC (Standardized Measurement
of Equipment, Particulate Airborne Concentration) is not yet available, it is
recommended to carry out the measurement during the FAT.
After the installation of the containment and before commencing operations, the
SAT (Site Acceptance Test) should be carried out. During the SAT, all the func-
tions are retested in operation, including all interfaces. All documents, such as,
for example, certificates for synthetic materials with direct contact with the
product, are checked for completeness, correctness, and allocation to the
installed components.

Following the successful completion of the SAT, operations may commence. In
general, the commencement of operations will be carried out with a surrogate
product with similar characteristics, or with the intended product itself. At this
point it is recommended to carry out containment measurements in shorter
intervals. Once the containment measurements have been validated within the
required range, the production with the highly potent substance can begin.
ID
During the FAT and SAT, number:
training 1037317
should be held for operators, maintenance,
and cleaning personnel. The trainings for the equipment operators should be
repeated regularly and the training success validated.
Containment Manual
4.5 Production, Use of Equipment

When routine operation is underway, regular as well as unannounced monitoring
of the containment should be carried out.
As part of the regular monitoring, the critical areas previously defined in the
monitoring plan must be checked.
In the case of unannounced monitoring, it is recommended to carry out wipe

tests on selected points of the containment and on the clothing and hands of the
operators. This test can help to verify the proper usage of the system.
After every product change, the cleaning of the equipment should be validated
on all potentially contaminated surfaces. The surfaces of parts that come into
contact with the product should be visually inspected for damage or scratches.
Enhanced monitoring should be carried out at the start of production of every

new product. It is also recommended that operators should wear adjusted
personal protective equipment during this phase, until the safety-related effec-
tiveness of the installation and the containment have been confirmed by the
monitoring of the containment.
In addition to the routine operation, a safety concept should be elaborated for

what to do in case of an incident, and the workers should be appropriately
trained. For example, how should the operators react after a containment breach
has been detected with an isolator?
Moreover, there should also be a safety concept for disruptions and the neces-
sary intervention activities during normal operation. It must be ensured that
workspaces and other equipment are not contaminated during the intervention.
4.6 Repair and Maintenance

A containment system only works for as long as regular maintenance and repair
activities are carried out. Even the slightest wear and tear can lead to a contain-
ment breach and this is especially valid for direct and mechanically moved
containment systems, such as e. g. split valve systems, split cone systems, and
rapid transfer ports, but also for indirect containment systems, such as e. g.
process filter systems, exhaust air filters, seals for process systems, flange
joints, tri-clamp connections, flexible connections, and shaft seals. All these
systems are subject to wear and tear and must therefore be checked and main-
tained in regular, specified intervals.
The repair and maintenance plan should not be regarded as a rigid document,
but should rather be adapted regularly in light of new insights.

Wear and tear is also product-dependent and it may, therefore, be necessary to
adopt product-specific repair and maintenance plans (especially in multipurpose
equipment) e. g. due to the abrasive characteristics of certain substances.
ID number: 1037317
Maintenance of equipment, workspaces, and containment systems should be
simple to access and carry out. This should already be considered during the
detailed planning and discussed with the suppliers. If certain parts may only be
maintained by the supplier, then it must be checked whether the supplier can
provide suitable rooms and trained personnel, since highly potent particles could
be released by dismantling activities.
Containment Manual
It must also be ensured that no cross-contamination or contamination with

foreign substances is caused by the supplier through the maintenance of parts
from different customers. The supplier should be made aware that necessary
prescribed protective measures must always be taken.
4.7 Cleaning
Cleaning of the containment is dependent on the type of cleaning required, the
product being manufactured, and the hygiene design of the installation.
The following types of cleaning may be employed:
▪▪ Air Cleaning:
Air cleaning is used to purify surfaces from product residues using air nozzles.
This is possible for products manufactured in a containment for single purpose
operation and for which an “optically clean” cleaning result is sufficient for the
surfaces. This is not a suitable method for the production of highly potent
substances, because the systems must be opened in order to check the
cleaning result.
▪▪ WIP (Washing in Place):
WIP is used when dealing with a very complex installation, or also when the
product that is to be produced in the installation, or its properties in relation to
the cleanability of the surfaces are not known. WIP is also used in multipur-
pose installations. Although the surfaces are cleaned by WIP methods, critical
parts or parts which are difficult to access must subsequently be cleaned
manually. Care must be taken with this type of cleaning that no product dusts
are released when dismantling individual components. All areas within the
system must be sufficiently wetted with cleaning liquid before being dismantled.
▪▪ CIP (Cleaning in Place):
CIP is used for production equipment that been developed and designed such
that the cleaning always leads to a value below the required threshold and
can be carried out automatically without the need for a follow-up manual
cleaning step. CIP is in principle product-dependent must thus be validated
for every product individually.
▪▪ SIP (Sterilisation in Place):

SIP represents the automatic sterilization of the installation after cleaning.
All of the above-mentioned methods require validation of the success of the

cleaning. The validation must be performed at critical points based on the
required threshold limits. It must be possible to adequately detect product resi-
dues at these critical points. Usual methods include final rinse and wipe tests, or
combinations of both.
ID number: 1037317
As already mentioned, surfaces may be subject to mechanical stress or abra-
sion from the product and must therefore be checked regularly.
Numerous cleaning media are available including water in different qualities, but
also various solvents and caustic solutions. It should be taken into account when
Containment Manual
selecting materials that caustic solutions and solvents may corrode certain
surfaces.
4.8 Decommissioning
The shutdown or decommissioning of an equipment or facility should also be
considered in the planning phase.
The requirements for the shutdown can be very different. In the case of multipur-
pose equipment, the equipment is designed for use with different products.
Generally, cleaning methods exist for switching from one product to another that
may also be used for the shutdown.
The situation may be more difficult for equipment that is only used for one
product – in particular when the product is produced in a so-called “dedicated
equipment”, due to its highly potent properties. The utilization of all parts that
come into the contact with the product must be checked and evaluated in great
detail. For certain substances or groups of substances (see also section 2.6.1)
further utilization may be prohibited.
The disposal of contaminated equipment parts, technical equipment, parts of the

workspaces (walls, ceilings, floors, airlocks including fittings), and ventilation
systems must be carried out by specially trained personnel. Sale and/or disposal
of the parts following decontamination must be documented in written form.
To what extent the building and adjoining installations may be further utilized
must be evaluated based on a risk analysis.

ID number: 1037317
Containment Manual

ID number: 1037317
5 Process Requirements

ID number: 1037317
ID number: 1037317
ISPE D/A/CH COP CON 5 Process Requirements
Containment Manual
5 Process Requirements

This chapter describes the requirements placed on the containment by the various pharmaceutical
processes used, and in the production of active pharmaceutical ingredients (APIs).
5.1 Pharmaceutical Production
5.1.1 Dispensing Area (Assembling, Weighing, Mixing, Dissolving)

The dispensing of pharmaceutical substances effectively refers to the dosing and mixing of the APIs
with a liquid, resulting in a solution or suspension or mixing with other solid excipients resulting in
an intermediate as starter for the manufacture of several solid dosage forms.
In the aseptic production of parenteral drugs, the bulk product must be sterile-filtered and continu-
ally handled in a sterile manner in subsequent steps (e. g. fill and finish).
Typical Steps in a Dispensing Process:
▪▪ Sterilization of the equipment, if required (SIP),
▪▪ Introduction of solvent e. g. WFI in a mixing vessel,
▪▪ Dosing/weighing of the APIs,
▪▪ Introduction of the APIs into the mixing vessel,
▪▪ Stirring,
▪▪ Adjusting temperature,
▪▪ Measuring and adjusting pH value as required,
▪▪ Sampling,
▪▪ Sterile-filtration,
▪▪ Transfer to filling machine.

ID number: 1037317
5 Process Requirements ISPE D/A/CH COP CON
Containment Manual
Fig. 4 Schematic Overview of a Mixing Equipment with Containment Isolator
In terms of operator protection, the addition of highly active pharmaceutical ingredients to the
blending vessel is seen as particularly critical. In this step, the pure active ingredient is weighed in
powder form and added to the mixing vessel. This is usually a manual step. At this point in time the
active ingredient is 100 % concentrated, and it is only through the mixing step that it is diluted. It is
easier to realize operator protection in the diluted liquid state.
From a containment perspective, critical steps include:
▪▪ Weighing the APIs,
▪▪ Addition of the APIs to the mixing vessel,
▪▪ Sampling,
▪▪ Pressure equalization of the vessel,
▪▪ Cleaning the mixing equipment.

5.1.1.1 Weighing the Active Pharmaceutical Ingredients
In the pharmaceutical industry, the weighing of APIs is often a manual process, and it should be
taken into consideration that the container in which the active agent is delivered can be suitably
opened under containment conditions.
ID number: 1037317
Containment Manual
5.1.1.2 Inwards and Outwards Transferring
Introduction into Containment
In order to transfer the API, the delivery containers can either be placed entirely inside the contain-
ment, or docked onto the containment externally.
The following transfer systems could be used, for example:
▪▪ Drum Docking Systems,
▪▪ Rapid Transfer Ports (RTP),
▪▪ Split Valve Systems,
▪▪ Airlock Chambers with Cleaning Systems,
▪▪ Foil Tube Systems/Bag-In/Bag-Out Systems,
▪▪ Air Barrier Systems,
▪▪ Single-Use Foil Transfer Systems with Special Connections.
Fig. 5 Isolator with RTP

The APIs are removed from the source container either manually or by means of transport systems
(e. g. pneumatically), then dosed and weighed with a balance. This is carried out within a contain-
ment unit to protect the operator.

Even with an automatic dosing system, attention must be paid to operator safety e. g. when
connecting the source container to the dosing device and when cleaning and disassembling the
dosing device.
ID number: 1037317
Once the APIs have been correctly dosed, they can either be directly transferred into the mixing
vessel or they can be transferred out of the dosing device into containers/bags in order to carry out
the mixing at a later point in time.
Containment Manual
Outwards Transfer
Residues of APIs, containers/bags used to weigh APIs, waste, and samples must be transferred out
of the containment via airlock systems. In principle, the same transfer systems used for the intro-
duction may be used. Often, however, the mode of operation/procedures may be different.
5.1.1.3 Transferring the APIs to the Mixing Tank
After weighing, the APIs are added to the mixing tank. For small batches it is possible to do this
directly in the containment unit e. g. with a glass beaker in an isolator.
In the case of larger batches, the mixing tank may be an integral part of the containment unit or
docked on to the containment externally.
Fig. 6 Isolator with Mobile Mixing
Integrated/Fixed Systems
The mixing vessel is built in to the floor of the containment unit. In order to transfer the APIs, the lid
of the mixing vessel in the containment unit is opened and the active agent dissolved in the liquid.
Generally, this is mostly only possible with small vessels.
Larger vessels Belo
are connected with the containment
Horizonte, Minas unit such that a part of the upper floor is inte-
Gerais,
grated into the containment unit, or the containment unit and the vessel are connected through a
IDconnection
downpipe. With these fixed number: 1037317
systems, in the containment unit mostly only a one hand
hole of the vessel is opened in order to add the API. A disadvantage of the fixed systems is that it
is difficult to weigh the vessel.
Containment Manual
Fig. 7 Example of Integrated

Systems
Mobile Systems
In this case either the blending vessel is mobile and is docked onto the containment unit, or the
containment unit is mobile and is docked onto the stationary vessel.
The following types of docking systems may be used:
▪▪ Rapid Transfer Ports (RTP),
▪▪ Split Valve Systems,
▪▪ Air Barrier Systems as a Containment around the Vessel.
Note: If one component of the system is to be implemented pressure-tight, then all other compo-
nents – such as e. g. the docking system – also have to be implemented pressure-tight.
5.1.1.4 Connecting Product Tubes/Pipes
The outflow of substances must be avoided when connecting or disconnecting tubes and pipes. The
operator must also be protected from APIs in diluted liquid form. In the case of unnoticed leakages,
it is possible that liquid accumulates to higher quantities. When the liquid has dried, the active agent
is left over as a powder residue outside the containment unit and endangers the operator.
When reconnecting pipes, it must be ensured that the correct connections are made before media
valves are opened.

Depending on the product, pipes and/or tubes may need to be sterilized and operated in a sterile
manner following the connection. This can be done using sterile tube connections or steam-through
connections. In this case single-use materials are often used.
ID number: 1037317
Containment Manual
Fig. 8 Mixing Vessel Docked to a Filling Panel
5.1.2 Granulation and Drying

Granules are created as an intermediate product form in the course of pharmaceutical manufac-
turing to enable the further processing of powders and ultimately attain the various different solid
dosage forms (tablets, capsules). This can be achieved by compression or by the addition of a
binding agent. A differentiation is made between wet and dry granulation.
Depending on the batch size, from the kilogram scale in the lab up to several tons in production, the
manufacturing equipment can have very different dimensions. The actual granulation process itself
always takes place in a closed environment in the methods mentioned here. From the perspective
of operator protection and GMP, critical points are the charging, discharging, cleaning, and repair/
maintenance of the production plant and peripherals, e. g. exhaust air and vacuum pipes must be
fitted with suitable filters, as product dusts can be carried away.
From a technical point of view, granules can be manufactured by two different process types; a
differentiation is made between agglomeration and desagglomeration granulation.
5.1.2.1 Mixer for Wet Granulation
Areas of Application:
▪▪ Production step for the manu-

This Document is licensed to facture of tablets
▪▪ Production step for filling

capsules
facture of instant powders
ID number: 1037317
Fig. 9 Open Wet Granulator (High Shear Mixer)
Containment Manual
Machine Design and Operating Principle:
The process unit of a wet granulator that comes into contact with the product consists basically of
the vessel interior (space and surface), a multipart mixing blade, and a crushing unit (chopper). The
powder components are usually dispensed from above. The dry powder components are homoge-
nized by the rotation of the multipart mixing blade. Following this, the granulation liquid is added and
the fast-rotating crusher (chopper) is switched on to break the granules down to the required size.
Under a continuous mixing and crushing process, the granulation liquid is added to the previously
dispensed and dry-mixed powder components until a dough-like consistency is reached. The air
which is displaced by the addition of the granulation liquid is led off through a filter. Product and
residues are discharged through a discharge opening. The granular material prepared in this way
will then usually undergo a wet sieving procedure (see section 5.1.3).
Critical steps from a containment point of view are the charging of the powder components,
the (complete) discharging of the granular material, and the cleaning.
Process Step Examples of Technical Solutions
Powder dispensing • Use of pneumatic transfer systems

• Use of split valve systems or split cone systems
• Flexible transfer systems
• Integration in isolator (small systems)
Discharge of granular • Via split valve systems into containers

material • Fixed piping e. g. to the wet mill
• Pneumatic powder transfer systems
Cleaning • Integration in isolator (small systems)

• Intervention via cleaning port (residual layer) WIP/CIP systems
• Manual cleaning in the isolator (small systems)
Other Notes:
▪▪ Possible product contamination on the shafts and through holes of the mixer and the crusher
caused during operation and cleaning (see Fig. 10). Contamination may occur in mechanical
working parts in the case of faulty shaft seals.

Fig. 10 Shafts and Through-Holes in a Wet Granulator
ID number: 1037317
Containment Manual
5.1.2.2 Mixer for Spray Granulation

facture of tablets
▪▪ Production step for filling

capsules

facture of instant powder
Fig. 11 Spray Granulator
The process unit of a wet granulator that comes into contact with the product consists basically of
the vessel interior (space and surface), mixing blades, a crushing unit, and a spray nozzle. The
powder components and binding agents are generally dispensed from above. The dry powder
components are homogenized by the rotation of the mixing blades. Following this, the granulation
liquid is added and the fast-rotating crusher is switched on to break the granules down to the
required size.
Following the dispensing and mixing of the dry powder components, the binding agents are then
added in a second step. During the continuous mixing and crushing processes, a liquid, such as
e. g. purified water, is added until a dough-like consistency is attained. The liquid is added via a
spray nozzle and compressed air fed in parallel ensures a fine distribution of the resulting drops of
liquid. The displaced air is fed off through a filter. The finished product and residues are discharged
via the discharge opening. The granular material prepared in this way then usually undergoes a
further dry sieving procedure (see section 5.1.3).
Critical steps from a containment point of view include the addition of the powder compo-
nents, the (complete) discharging of the granular material, and the cleaning.
Powder dispensing • Use of pneumatic transfer systems

•
•
•
Use of split valve systems or split cone systems
Flexible transfer systems
Integration in isolators (small systems)
Discharge of granular
material Mr. Bruno• • Via split valve systems into containers
Henrique
Fixed Santiago
piping e. g. to the wet mill Lima
• Pneumatic powder transfer systems
Cleaning
• Integration in isolators (small systems)
ID• • number: 1037317
Intervention via cleaning
WIP/CIP systems
port (residual layer)

Containment Manual
Other Notes:
▪▪ Possible product contamination on the shafts and through holes of the mixer and the crusher
caused during operation and cleaning. Contamination may occur in mechanical working parts in
the case of faulty shaft seals.
Fig. 12 Shafts and Through-Holes

in a Wet Granulator
5.1.2.3 Fluid-Bed Granulator
▪▪ Process step for the manufac-

ture of tablets
▪▪ Process step for filling capsules

ture of instant powder
Fig. 13 Principle of the Fluid-Bed Granulation
Machine Design and Operating Principle

The processing unit of a fluid-bed granulator that comes into contact with the product consists
essentially of the processing chamber with an integrated product filter, a product container with a
sieve bottom, and a spray nozzle. Powder components and binding agents are usually dispensed
from above onto the sieve bottom. While the granulating fluid (e. g. purified water, or organic solvent)
is sprayed in with compressed air, the powder bed is swirled and tempered in a continuous stream
of air. Belo Horizonte, Minas Gerais,
ID number:
Once the defined process parameters 1037317
have been reached, the liquid is added via a spray system
while the swirling is ongoing. The dusts carried away by the turbulent air stream are separated out
by a product filter in the dome of the fluid-bed granulator and fed back into the process through
continuous cleansing of the product filter. The powder is prevented from leaving through the air
inlets by an integrated fine-mesh sieve bottom. Once the process is completed, the product is
discharged into the product container. The granulate produced in this way usually undergoes a dry
sieving process (see section 5.1.3).
Containment Manual
Fig. 14 Product Filter
Fluid bed granulators can also be used as Fluid bed Dryers.
Critical steps from a containment point of view include the addition of the powder compo-
nents, the complete discharge of the granulate, the cleaning, and the sampling.
Powder charging • Sucking in through vacuum

• Use of split valve systems or split cone systems
Discharge of granular • Via split valve systems or split cone systems into containers
material • Fixed piping e. g. to the dry mill
• Pneumatic transfer systems
Cleaning • WIP /CIP systems

Sampling • PAT online measurement

• Use of sampling systems
• Sampling in the isolator (small systems)
Other Notes:
▪▪ Fine particles of the powder mixture may penetrate into the product filter and contaminate the
exhaust air duct.

ID number: 1037317
Fig. 15 Exhaust Air Duct with Product Fig. 16 Exhaust Air Flap with Product
Adhesions Adhesions
Containment Manual
5.1.2.4 Single Pot Mixer Granulator

ture of tablets
▪▪ Process step for filling capsules

ture of instant powder
Fig. 17 Single Pot Mixer Granulator
The processing unit of a single pot mixer granulator that comes into contact with the product
consists of a combination of a high shear mixer with a conical sieve mill. The mixing chamber is
heatable, so that it is possible to simultaneously dry the granular material.
The functions and critical steps from a containment perspective can be considered the
same as for sections 5.1.2.1 (Desagglomeration Granulation – Wet Granulation) and 5.1.3.1
(Milling/Conical Sieve Mill).
5.1.3 Comminution
5.1.3.1 Milling
In the pharmaceutical industry, the milling process step is used for example for the following:
▪▪ Crushing agglomerates of raw materials prior to their usage,

▪▪ Crushing agglomerates during a manufacturing process (e. g. after dry-mixing several raw mate-
rials or following fluid-bed drying),
▪▪ Producing defined particle sizes for subsequent processing (e. g. tableting),

▪▪ Crushing intermediate
Beloproducts for their subsequent
Horizonte, processing
Minas (e. g. crushing extrudates for the
Gerais,
production of a tablet mixture).
ID number: 1037317
The technical definition of crushing may be described as “overcoming the internal cohesion of a
solid material through use of external stress”. Crushing may also be described as grinding, microni-
zation, granulation, and pulverization. A differentiation may be made between wet crushing (e. g.
conical classifier or conical sieve mill) and dry crushing (e. g. jet mill).
Containment Manual
Crushing Principle Example Systems
Cutting • Granulators
• Cutting mills
Pressure between two surfaces • Strainer mills

• Shredders
Impact against surfaces or particles against particles • Mechanical impact mills

• Jet mills
Pressure and shear • Mills with grinding media
The following list describes some examples of crushing systems used in the pharmaceutical
industry.
Conical Sieve Mill/Conical Classifier Mill
▪▪ Desagglomeration (wet gran-

ules) before fluid-bed drying
▪▪ Desagglomeration (dry gran-

ules) following fluid-bed drying
▪▪ Sieving of powder mixtures

before subsequent processing
(e. g. before tableting)
Fig. 18 Conical Sieve Mill
The material to be milled is added from above onto a rotating rotor. The rotor is located at a defined
distance from a conical sieve or perforated plate. The rotor presses the material against the sieve/
plate and crushes it. The crushed particles then fall through and are carried out.

Suitable for To Note
Closed product handling Only possible in combination with an inlet and outlet system
Fixed installation in a system Rotating parts must be detachable
Belo Horizonte, Minas
Surfaces Gerais,
coming into contact with the product must be
reachable
ID number: 1037317
Simple system construction It must be possible to check sieves for damage before
assembling and after usage
Downloaded on:It must
WIP/CIP cleaning
1/15/19 11:37 AM
be possible to wet all contaminated surfaces before
opening or disassembling the system
Containment Manual
Mechanical Impact Mills
▪▪ Desagglomeration
▪▪ Comminution of intermediates
(e. g. extrudates, ribbons, or
flakes)
▪▪ Milling of APIs
Hammer Mill
Fine Impact Mill
This Document is licensed to Fine Impact Mill
Fig. 19 – 21 Mechanical Impact Mills

ID number: 1037317
The material to be milled is added from above and accelerated by means of various milling tools
such as hammers, beaters, rotors, and pins. The accelerated particles impact against each other or
a fixed surface (sieve) at high speed and are thus broken down in size. The sieve encloses the
complete milling tool and thus defines the particle size. The crushed particles are then carried
downwards and out.
Containment Manual
Closed product handling Only possible in combination with an inlet and outlet system

Surfaces coming into contact with the product must be
reachable
WIP/CIP cleaning It must be possible to wet all contaminated surfaces before

Critical points from a containment perspective for all of the mentioned mill types are the
introduction of the material to be milled, the complete discharge of the milled material, and
the cleaning.
Process Step Examples of Technical Containment Solutions
Addition of mill material • Use of pneumatic transfer systems

• Use of split valves and split cones
• Integrated in an isolator
• Integrated (fixed assembly) in a process
Discharge of the milled • Via split valve into a container

material • Pneumatic transfer systems
• Integrated (fixed assembly) in a process
• Integrated in an isolator
Cleaning • WIP/CIP systems

• Manual cleaning within an isolator
Other Notes:
Possibility of product contamination at the shaft through holes due to operation and cleaning
processes. In the case of defect shaft seals, contamination in the drive section may occur.
5.1.3.2 Sieving – Sifting
In the pharmaceutical industry, the sieving process step has several usages, such as e. g. the
following:

▪▪ Separation of a disperse solid mixture into various fractions according to particle size or density,
▪▪ Removal of undesirable particle sizes from powder mixtures before subsequent processing,

▪▪ Classification of particle sizes,
▪▪ Removal of impurities,
ID number: 1037317
▪▪ Control screening,

▪▪ De-dusting of tablets.
Containment Manual
Principle Example Systems
Sieving: • Vibration sieving machines

Classification using gravity depending on geometrical charac-
teristics by means of meshes or perforated plates
Screening: • Air classifiers

Classification using gravity or centrifugal force depending on • Classifier mills
the rate of descent in an air stream
The following list describes the most common sieving systems, but in no way claims to be complete.
Vibration Sieving Machines
▪▪ Classification of particle sizes
▪▪ Control screenings, removal of

impurities
▪▪ De-dusting of tablets
Fig. 22 Vibration Sieving Machine
The sieving machine is mostly loaded with the material to be sieved from above. The material is
vibrated through a series of sieve stacks one on top of the other. Each of the sieve stacks has a
different mesh size. They are arranged in order with the coarsest mesh at the top and the finest
mesh at the bottom. Each of the sieve stacks has its own side outlet so that individual fractions of
the product may be separated.
Suitable for
To Note
Mr. Bruno Henrique

Closed product handling
Santiago Lima
Only possible in combination with an inlet and outlet system
Belo Horizonte,
Fixed installation in a system
Minas Gerais,
The sieves must be detachable
Surfaces coming into contact with the product must be reach-
ID number:
able
1037317
Dust-free (or near dust-free) discharge of every fraction must
be possible
It must be possible to check sieves for damage before and
after usage

Containment Manual
Classifier Mills
▪▪ Classification of particle sizes
▪▪ Separation of a desired particle

size
Fig. 23 – 24 Air Classifiers, Classifier Mills

The air classifier/sieve
Belomill is mostly loaded with
Horizonte, Minasmaterial Gerais,
from the side. The powder is picked up by
an air vortex generated in a cyclone. Depending on the strength of the air stream, lighter particles
are carried upwards whereIDtheynumber:
are engaged by 1037317
a turbine wheel and transported out to the side.
Heavier particles fall out of the machine under the influence of gravity. The particles are subject to
two principle forces: drag from the air and the centrifugal acceleration of the classifier. Fine particles
pass through the classifier and are carried out with the air/gas stream. Coarser particles are
rejected by the classifier wheel and carried out downwards. Separation of the fine particles from the
air/gas stream is usually achieved with a filter.
Containment Manual
Closed product handling Classification can only be carried out in a closed system

Surfaces coming into contact with the product must be
reachable
The air/gas stream must be freed from highly potent dusts by
means of suitable filters

Critical points from a containment perspective for all the mentioned sieve types are the
introduction of the material to be sieved, the complete discharge of all fractions, and the
cleaning.
Introduction of material to • Use of pneumatic transfer systems

be sieved • Use of split valves and split cones
• Integration in an isolator
• Integration (fixed assembly) in a process
Discharge of the sieved • Via split valve into a container

fractions • Pneumatic transfer systems
• Integration (fixed assembly) in a process
Cleaning • WIP/CIP systems

5.1.3.3 Examples for the Usage of Milling and Screening Equipment in Containment
Impact mill in a closed system

(fixed installation)

ID number: 1037317
Fig. 25 Fixed Installation
Containment Manual
Impact Mill and Laboratory Mill in an

Isolator
Fig. 26 – 27 Mills in an Isolator
5.1.4 Tableting, Coating, Blistering
5.1.4.1 Tableting
Tableting, i. e. the manufacture of tablets, is carried out by means of tablet presses.
The pharmaceutical substance is mixed and homogenized together with filling material in a mixer
or blender. By means of a transfer and/or feed system, the homogenized powder is then forwarded
to the dies and punches of the tablet press via the filling shoe, and pressed into tablets. The finished
tablets are ejected and subsequently de-dusted e. g. via a vertical conveyor before finally falling into
a transport container.
Tablet presses and the associated equipment such as metal detectors, de-dusters, transport
containers, etc., are usually located in a cleanroom. In the case of small tablet presses, this clean-
room can also be an isolator.
In order to minimize dust emissions from tablet presses, these are now built in containment
versions. These versionsID
differnumber: 1037317
from others in that there is e. g. better sealing from the underlying
drive compartment, viewing windows with glove ports, split valve systems to introduce materials,
hygienic design, or less additional fittings among others. Tablet presses are CIP/WIP capable, but
the rotor may need to be pre-cleaned and then removed by swinging it out of the unit if the punch
material is susceptible to corrosion. The rotor must then be taken for cleaning in a suitable transport
unit.
Containment Manual
Fig. 28 Tablet Press and Periphery
Critical steps from a containment perspective include the dispensing of material, the subse-
quent devices such as metal detectors and de-dusters, and cleaning.
Charging of material • Use of pneumatic transfer systems

• Use of split butterfly valves or split cone valves
• Integration in an isolator (small systems)
Filling area • Enclosure, closed systems, local suction extraction, working under nega-
tive pressure

Production interventions • Via control programs, glove ports
Connected apparatus • Use of glove boxes, isolators, closed connections (flexible, fixed)
• Split butterfly
Mr. Bruno
Product discharge Henriquevalve systemsSantiago Lima
• Local suction extractions
Cleaning Belo• Horizonte, Minas

Use of WIP systems, wetting Gerais,
the surfaces in contact with product before
ID number: 1037317
opening the workspace
Containment Manual
Extraction of tablets for in-process control on a tablet press
When manufacturing tablets, samples must be taken from the ongoing production operations at
regular intervals. The samples are immediately fed into an in-process control and have a direct
influence on the machine settings, and thus also on the quality of the tablet batch being produced.
Typical in-process controls may include:
▪▪ Hardness or breaking strength,
▪▪ Weight,
▪▪ Thickness, length, width, diameter of the tablet.
▪▪ Sampling
▪▪ Sorting into “good production”
▪▪ Sorting into “bad production”
Fig. 29 Sorting Chute on a Tablet Press
Operating Principle:
The selection between bad production, good production, and sampling is made using a sorting
chute on the tablet press. The appropriate channel on the sorting chute is opened by means of a
motor-driven and/or pneumatic-driven gate.

Closed product handling In the case of tablet discharge and operation with highly
potent components, a disruption may only be remedied
Mr. Bruno Henrique Santiago Lima in full protection PPE
Tablet samplingBelo Horizonte,

with highly potent compo- Minas
The housingGerais,
of the sorting chute must be a dust-tight
nents implementation, or located within a containment
WIP/CIP cleaning
ID number:It1037317must be possible to wet all contaminated surfaces
before opening or disassembling the system
Containment Manual
Critical points from a containment perspective are the discharge of samples, intervention
in case of a disturbance, and cleaning.
Discharge of samples • Use of split butterfly valves

• Use of continuous liners
• WIP/CIP cleaning of the complete installation without prior disassembly
(tablet press + sorting chute)
Intervention in case of • Integration in an isolator

disruption • WIP/CIP cleaning of the complete installation before disassembly
Cleaning • Integration in an isolator

• WIP/CIP systems
Tablet De-Dusters:
Tablet de-dusters are cleaning and deburring systems for tablet cores. The de-dusting and
deburring process is an important process step in order to be able to proceed with further
processing of the tablets (e. g. coating or blistering).
Tablet de-dusters are mostly used together with a tablet press and a metal detector, but also for
de-dusting capsules.
▪▪ De-dusting of tablet cores
▪▪ Deburring of tablet cores

Fig. 30 Upwards De-Duster
ID number: 1037317
Containment Manual
▪▪ Deburring of tablet cores
▪▪ De-dusting of tablet cores
Fig. 31 – 32 Deburrers
Upwards De-Dusters:
The deburring and de-dusting of the tablet cores are carried out along a perforated spiral. The
tablets or capsules are transported upwards in the spiral by means of vibration. The upwards
de-duster is connected to a suction unit which creates a stream of air in the spiral path. Dust
particles are carried off by the air stream and led down out of the device.
Deburrers Mr. Bruno Henrique Santiago Lima

Deburring and de-dusting are carried out in a rotating perforated drum. A spiral is located within the
ID number:
drum as a guide for the stream 1037317
of tablets or capsules. The deburring is connected to a suction unit
which creates a stream of air around the drum. Dust particles are carried off with the air stream and
led down out of the device.
Containment Manual
Closed product handling In the case of tablet de-dusting and deburring operations with
highly potent components, a disruption may only be remedied
in full protection PPE
Deburring and de-dusting of tablets The exhaust air outlet technology must be suitable for highly
and capsules with highly potent potent dusts
components

Critical points from a containment perspective are the introduction and discharge of
product, cleaning, intervention in case of disruptions, and the outlet air extraction.
Introduction of product • Use of split butterfly valves

(tablet press + de-duster)
Discharge of product • Via split butterfly valves into containers

• Pneumatic transfer systems
(tablet press + de-duster + container)
Intervention in case • Integration in an isolator

of disruptions • WIP/CIP cleaning of the complete installation before disassembly
Air extraction • WIP/CIP of the exhaust air tubes

• Integration of an H14 filter
• Push Push filter system
• BIBO filter system
• WIP/CIP of the exhaust air tubes and the filter system
Cleaning • Integration in an isolator

• WIP/CIP systems
• Manual cleaning within the isolator
5.1.4.2 Coating
Coating refers to the application of a film to cover a body; in the pharmaceutical industry mostly
tablets, dragees, or pellets. Coating can fulfil a variety of functions, including e. g.:
▪▪ Encapsulation of highly
Belo potent substances,
Horizonte, Minas Gerais,
ID number:
▪▪ Sustained release of active ingredient 1037317
(defined time, defined place of release),
▪▪ Neutralization of taste and smell,

▪▪ Appearance,
Containment Manual
▪▪ Barrier against environmental influences (air, moisture, light, etc.),
▪▪ Color labelling, brand identification, printing.
Spray Coating
If the coating is carried out in a fluid bed equipment, then this is defined as spray coating. This can
be done in continuous manufacturing or in batches. Depending on the airflow, one can differentiate
between top spray coating, bottom spray coating, and tangential spray coating. The assembly of the
spray coater is similar to that of a fluid bed granulator.
The components of a spray coater that come into contact with the product are essentially comprised
of the processing chamber with integrated product filter, a product container with sieve bottom, and
the spray nozzle. The coating material is applied either as a solution, a suspension, or as a melt.
While the coating material is being sprayed in together with compressed air through the spray
nozzle, the material to be coated is swirled around and tempered while kept in a continuous stream
of air. In the case of tangential spray coating, the material to be coated is kept in uniform motion by
a motor-driven disk.
Fig. 33 Spray Coater (Top Spray) Fig. 34 Spray Coater (Bottom Spray)
Critical steps from a containment perspective include the charging of the material to be
coated and the cleaning, as spray coating is carried out in a closed system under negative
pressure..

Charging • Use of pneumatic transfer systems
• Use of split butterfly valves or split cone valves
Cleaning Belo Horizonte,

• Intervention viaMinas
cleaning portGerais,
• WIP/CIP systems
ID• number:
Manual cleaning in1037317
an isolator (small systems)
Containment Manual
Drum Coating
The other type of coating is carried out in a drum coater. This can also take place in continuous
manufacturing or batch mode.
In the case of drum coating, the material to be coated is filled in a perforated drum which is then
rotated at a set rotational speed during the coating process. The coating material is applied via a
nozzle arm equipped with several spray nozzles distributed along the length of the apparatus. The
material to be coated is mixed inside the drum by means of guiding plates or vanes. The material is
dried via a continuous air stream from outside through the perforated drum. Turbulence at the nozzle
outlets can be kept low using horizontal airflow. The input air must be conditioned (temperature,
humidity) and filtered (purity), the exhaust air must be filtered.
Drum coaters are CIP/WIP capable and to achieve this, diverse cleaning nozzles must be fitted
within the apparatus.
Fig. 35 View inside a Drum Coater
Critical steps from the containment perspective include the charging of the material to be
coated and the cleaning, as the drum coating process is carried out in a closed system
under negative pressure.

Cleaning • Use of WIP/CIP systems

5.1.4.3 Blister Packaging
A blister pack is a transparent packaging or push-through packaging (pharmaceutical term) which
is used for packaging tablets. The cover foil is mostly made of aluminium. The tablets are arranged
in individual cavities or pockets in a plastic or aluminium sheet, and sealed in by the cover foil.
ID number: 1037317
Packaging of the tablets, sugar coated tablets etc., into blister packs is done in blister machines, or
blisterlines in which a series of different processes can run. From a containment perspective, only
the charging of the tablets to be packed, right up to the point at which no dust emissions can occur,
need be considered.
Containment Manual
Fig. 36 Blister Machine
Critical steps from a containment perspective include the charging of the tablets to be
packed and the cleaning of the feeding point.
Charging • Use of isolators, RABS, or glove boxes

• Active mouseholes at the foil feeders
Cleaning • Use of WIP/CIP systems
5.1.5 Liquid Filling: Aseptic/Non-Aseptic

In pharmaceutical production, liquid medicines for oral use are typically filled glass bottles, liquid
medicines for parenteral use are filled in ampoules, vials or prefilled syringes. Aseptic bottling refers
to the process of filling a sterile liquid into a sterile packaging material under aseptic conditions, and
subsequently sealing the packaging material.
The following packaging materials are particularly common.
5.1.5.1 Ampoules
Ampoules come in a variety of designs, and are mostly containers made of special glass that are
used for parenteral injection of medicines. Ampoules are made from tubular glass and closed off by
melting using a gas burner with an open flame.
A typical process sequence comprises washing and drying the glass containers, heating and
cooling in a hot air tunnelID number:
(continuous operation),1037317
filling, and melting closed. Following this, the finish
packed medicine leaves the containment via a small hole (mousehole).

Critical steps from a containment perspective with respect to the protection of the opera-
tors, are cleaning, and glass breakage during production, as this could lead to the release
of liquid substances. Substances are not present in powder form.
Containment Manual
5.1.5.2 Vials
Vials are small bottles that may be closed with a rubber stopper. The rubber stopper is pressed onto
the bottleneck by means of a crimp cap made of aluminium.
A typical process sequence consists of washing and drying the glass container, heating and cooling
in a hot air tunnel (continuous operation), filling, positioning the stopper, positioning the crimp cap
and crimping it around the edge. Following this, the finish packed medicine leaves the containment
via a small hole (mousehole).
For critical steps, see section 5.1.5.1.
5.1.5.3 Disposable Syringes
Disposable syringes are mostly used as so-called ready-to-fill syringes, i. e. they can be filled
directly without the need for further sterilization. The syringe consists of a cylindrical cavity with a
movable plunger inside it, and a hollow needle on the other side.
A typical process sequence comprises introducing the ready-to-fill syringes into the overpack (tubs),
filling the syringes, and applying the stoppers. The finished packed medicine (in pre-filled ready-
to-use syringes) then leaves the containment via a small hole (mousehole).
For critical steps, see section 5.1.5.1.
5.1.6 Capsule Filling
General Information
In pharmaceutical production, powder, pellets, tablets/micro tablets, microdosing medicines, and

combinations of the various solid and liquid bulk products are dispensed in hollow elastic bodies of
various sizes; so-called hard capsules. From an occupational hygiene point of view, filling capsules
with solids is more critical than with liquids, so the focus of this section is therefore restricted to the
filling with solids. The capsule protects a bulk product, such as a powder, from physical and chemical
influences arising from the climatic surroundings. Products that are light-sensitive, temperature-
sensitive, or hygroscopic are especially suitable for encapsulation in hard capsules.
Hard capsules are made of two halves (body and cap) which may be pushed into one another.
These empty capsules are produced industrially by means of a dipping process. The appropriate
size is individually adjusted for each medicine.
Capsule filling and sealing machines are available for various batch sizes ranging from laboratory
scale, to the production of clinical samples, right up to the commercial manufacture on an industrial
scale. GMP-critical aspects and work protection considerations must be taken into account during
the dosing of bulk products in a capsule filling and sealing machine. Two different areas of applica-
tion that have a significant influence on the GMP-critical and construction requirements of the
machine may be considered. On the one hand, there are machines in which highly potent products
are dispensed. In this case the primary goal is to prevent uncontrolled discharge of product dusts
from the machine, in order to protect the operators, the cleanrooms, and the environment from
ID number: 1037317
contamination (containment machines). On the other hand, there are capsule filling and sealing
machines that do not place these high requirements on work and operator protection.
Containment Manual
Machine Assembly:
1 Capsule orientation and insertion in segment row 1

2 Capsule orientation and insertion in segment row 2
3 In-Process control empty capsules (tare weight) and sepa-
ration of capsule components
4 free
5 free (optional dosing station)
6 Presence detection capsule body and capsule cap (sensing)
7 Ejection of unopened capsules
8 Powder dosing station
9 free
10 free
11 Capsule capping station
12 In-Process control for filled capsules (gross weight)
13 Ejection of bad capsules
14 100 % weight control with x-ray technology
Fig. 37 Machine Assembly Capsule Machine
Empty capsules are introduced from the blank-capsule container. In the next step they are aligned
and separated into two halves; the lower bodies and upper caps. Only capsules that have been
successfully separated reach the subsequent filling station in which the capsules are filled with the
appropriate product in the exact dosage. The charge material (active ingredients, excipients, etc.) is
forwarded from a storage container into the dosing station. The lower capsule body is then filled
with the charge material in the dosing station.
The tare and gross weighing of the capsules ensures that they have been filled with the correct
amounts.
After filling, the capsule is closed by pressing the upper cap onto the lower body.
All capsules filled with powder that are not sorted out from the production process by the bad
capsule ejector fall into the run-off slide, where a sample of the good capsules can be taken at any
time. The good capsules then proceed from here to any docked-on periphery devices, such as e. g.
de-dusters, metal detectors, capsule control weighing units, and/or container distributors where the
capsules are packed in special packages gravimetrically or volumetrically.
The last step in the production cycle of the capsule filling and sealing machine is the segment
cleaning. In this, all segments are freed of product residues by means of compressed air in order to
create ideal conditions for the resumption of production with new empty capsules.
ID number: 1037317
Containment Manual
Fig. 38 Conventional Capsule Machine Fig. 39 Containment Capsule Machine
Critical steps and areas from a containment perspective are the introduction of the charge
material, the filling of the capsules, intervention during the production, docked-on equip-
ment, product discharge, and the cleaning of the equipment.

• Use of split butterfly valves or split cone systems
Filling area • Enclosure, closed systems, local air suction, working under negative
pressure
Production interventions • Glove interventions (glove ports)
Docked-on equipment • Use of glove boxes, isolators, closed connections (flexible, fixed)
Product discharge • Split valve systems

• Split cone systems
• Use of pneumatic transport systems
Cleaning • Use of WIP systems
5.1.7 Transfer from Equipment to Equipment

In order to get from one process step to another, the product must be transported. From a contain-
ment perspective it should be ensured that the transport container and the transport method are
suitable i. e. that the prescribed containment is adhered to and no substance is released.
Examples of suitableBelo
systemsHorizonte,
and methods can Minas
be found inGerais,
sections 5.2.6 “Transfer” and 6.1
“Primary Containment”.
ID number: 1037317
Containment Manual
5.1.8 Lyophilisation
The freeze-drying process, also known as lyophilization, is a common component of aseptic manu-
facturing processes in pharmaceutic and biotechnology production. Lyophilization is an established
process step used on an industrial scale to dry temperature-sensitive products as gently as possible
i.e. to retain their chemical structure, activity, and stability.
The freeze-drying process can basically be divided into three phases comprising the freezing of the
product, main (primary) drying, and post (secondary) drying
Phases
Freezing Primary Drying Secondary Drying
“Cristallation” Sublimation Desorption
Temperature
Pressure
Shelf Temperature
Pressure
Fig. 40 Phases of Freeze-

Time Drying – Simplified Depiction
The following process description is simplified and serves as an example for water-based products:
▪▪ Freezing:
After loading the installation, the product is frozen at atmospheric pressure. This phase defines
as far as possible the product structure by crystallization processes. Once freezing is complete,
the process vessel is subjected to negative pressure in order to create the starting conditions for
the subsequent process step.
▪▪ Primary Drying:
In the primary drying phase, the product is dried by sublimation of the solvent (water). The process
conditions for sublimation are product-specific and should be selected based on pharmaceutical
considerations.
In order to stabilize the process conditions, the required sublimation energy should be supplied to
the product and the resulting amount of vapor should be removed.
Belo
The completion of the Horizonte,
primary drying phaseMinas Gerais,
is characterized by the end of the sublimation process.
▪▪ Secondary Drying: ID number: 1037317
In this phase, any remaining solvent e. g. adsorptively bound water, is further removed until the
target value of the desired remaining moisture content is reached.
Containment Manual
Equipment Technology:
Freeze-drying is used in different production processes. Whereas in the food industry, for example,
freeze-drying installations are used in continuous production operations, they are generally used in
batch operations in the pharmaceutical and biotechnology industry.
In order to attain the process conditions for batch operations on a production scale, systems with
the following general setup are used.
Fig. 41 Freeze-Dryer
▪▪ Drying Chamber (1)
The drying chamber contains shelves with the product to be dried.
▪▪ Shelves (2)
The shelves are movable and connected with a heat transfer system. The product containers are
loaded onto the shelves. The product is normally contained in vials/primary packaging material with
fitted lyophilization stoppers (lyo stoppers, in place still open), or in trays. In the case of lyo
stoppers, the shelves are pressed together at the end of the freeze-drying process in order to
completely insert the lyo stoppers into the vials.
▪▪ Heat Transfer System (3)
The heat transfer system (3) services the shelf area i. e. to heat or cool it in accordance with the
process requirements. Heat transfer is applied to the shelves to a) cool during freezing, and b)
heat during drying.
▪▪ Ice Condenser (4)
The ice condenser serves to take up condensable water from the atmosphere in the freeze-dryer.
The condenser is connected to the drying chamber via a valve. The interior contains cooled
surfaces onto which the sublimated solvent (water) can condense respectively freeze out.
ID number: 1037317
Containment Manual
▪▪ Vacuum System (5)
The vacuum system is connected to the ice condenser. It serves to evacuate the drying chamber
and the ice condenser in order to create optimum conditions for the drying process and pump off
non-condensable gases.
Plant Control:
The plant control is connected with the sensors of the freeze-drying system and controls the drying
process in accordance with the recipe specifications by means of heating/cooling processes, the
evacuation, and the aeration of the plant.
Containment Integration (Closed RABS/Isolator):
When connecting production-scale freeze-drying installations to a containment, a closed RABs or

isolator, additional assembly groups and systems will be required in order to enable the loading and
unloading of the installation.
Feeding systems must be constructed with a space-saving design, and for this the integration of
loading/unloading stations combined with transfer conveyors are a largely established design
version. The filled primary packaging material (vials) are transported to the loading/unloading station
via conveyor belt. From there, they are transferred as a vial package with the aid of a pushing
device, a formatting surface, and a pivoting transfer plane onto the shelves of the freeze-drying unit.
On completion of the freeze-drying process, the vials are unloaded by means of a further pushing
device which is arranged at the rear of the drying chamber. The vial package is pushed back in the
direction of the conveyor belt in order to transport the vials to subsequent downstream systems.
Fig. 42 Patent WO 96/35090

This Document is licensed to “Feeding Systems for Treatment
Facilities for Materials Situated in
Bins or Containers”

The loading/unloading
Belostation has a baseplate
Horizonte, on which the
Minas containment is fixed based on sealing
Gerais,
surfaces. A docking frame, which surrounds the loading/unloading door of the drying chamber,
constitutes the interface ID
to thenumber: 1037317
freeze-drying unit. The containment is connected with the docking
frame with the aid of mechanically sealing compensation systems or inflatable seals. The loading/
unloading station as well as the freeze-drying area within the docking frame are part of the contain-
ment and are subject to the specified requirements of the containment with respect to tightness,
cleaning, and decontamination.
Containment Manual
▪▪ The loading/unloading stations can be equipped with WIP systems to support cleaning processes.
Cleaning is limited to surfaces of the loading/unloading system and defined areas within the
containment. Automatic cleaning of areas that are difficult to access, such as the return air
channels of the containment, can be integrated.
▪▪ The system design should take into account any specific requirements of an H2O2 decontamina-
tion within the interior of the containment.
Fig. 43 Integration of Multiple Freeze-Dryers Fig. 44 View Inside an Isolator Docked onto a
Freeze-Dryer
Plant and Process Characteristics of Containment Integration:
Processing of highly active or toxic products WIP cleaning of surfaces of feeding and product
transfer systems within the containment by integra-
tion of automatic or manual spray systems
Processing of highly active or toxic products Separation of highly contaminated and slightly
contaminated wastewater from the containment area
and the freeze-drying unit for subsequent waste-
water treatment
Processing of highly active or toxic products Filtration of exhaust gases from freeze-drying unit
and the containment
Processing of highly active or toxic products Use of dry running (oil free) vacuum pumps
Containment Connection Design of the freeze-drying unit with connection to

the containment
Containment Connection Plant equipped with semi-automatic or fully auto-
matic loading/unloading system
Containment Connection Integration with monitoring systems

Containment Connection Sloped design to enable WIP cleaning and drainage
Belo Horizonte,within
Minas Gerais,
the containment
ID number: 1037317
Other Notes:
If a vial filled with highly active substance should fall and break, the freeze-dryer will be contami-
nated. A potential carry-over to subsequent batches via surfaces and air ducts in the containment
is possible.
Containment Manual
5.1.9 Goods Receiving

All substances required for the production (active ingredients, excipients, etc.) must be received in
a separate area, also known as the incoming goods area, and sampled before further processing
such as e. g. storage or production. Sampling must be done under suitable safe conditions, as it is
possible in this step that substance to be sampled may be handled openly. When checking
non-toxic substances, a suitable PPE may be sufficient. When handling highly potent substances,
it may be necessary to place special requirements on the environment, processes, and personnel.
In this case, sampling must be carried out in sampling cabinets with the appropriate equipment, or
even in isolators.
Examples of suitable systems and methods can be found in section 6.1 “Primary Containment”.
5.2 Production of Active Pharmaceutical Ingredients (APIs)
5.2.1 Charging
In the production of active pharmaceutical ingredients (APIs), the starting materials/intermediates
are added to a reaction process which may comprise a number of synthesis steps. The starting
materials may be delivered in various different container types, such as e. g. big bags/FIBCs (Flex-
ible Intermediate Bulk Containers), barrels/drums, sacks, cartons, etc., and subsequently fed into
the production.
The first production step in the production of APIs is filling the starting materials into a reactor. The
materials used must be added in a safe and closed manner. As the starting materials are often not
in the correct portioned amounts for the required batch size, this process can be very different.
Central Dispensing and Weighing
The central weighing is referred to as dispensation or dispensing and takes place in a room sepa-
rate from the actual production. Containment technology used in dispensing must be adapted to the
toxicity and amounts of materials to be weighed. Dispensing can be carried out using gravity, or,
especially in cases where there is insufficient height in the room, by means of a conveyor system
such as e. g. a pneumatic conveyor.

ID number: 1037317
Containment Manual
Example of Use:
▪▪ Closed dispensing of drums and

sacks into big bags/FIBCs or
similar containers for transfer
within the facility
▪▪ Product crushing (e. g.

de-lumping, sieving)
▪▪ Dosing using scales
Fig. 45 Dispensing Large Amounts Using Gravity
Example of Use
▪▪ Closed dispensing of big bags/

FIBCs into containers/IBCs
using a pneumatic conveyor
system
▪▪ Equipment-internal transfer to
production
▪▪ Dosing using pneumatic

conveyors
Fig. 46 Dispensing Large Amounts

Using Pneumatic Conveyor
Example of Use:
▪▪ Portioning of small amounts

e. g. from drums into a container
such as a bag
▪▪ Integrated weighing
▪▪ Closed transfer of a product to

This Document is licensed to the API production

Fig. 47 ID number:
Dispensing Small Amounts Using Gravity 1037317

Direct Weighing and Filling into the Reactor
Direct filling into the reactor takes place in the production area. The starting materials are fed into
the process either by means of gravity or pneumatic conveyors. The direct feed of starting materials
Containment Manual
helps to avoid intermediate steps such as central weighing, but can lead to an increase in time
required, as fine dosing is carried out directly during production.
Example of Use:
▪▪ Closed filling from drums into a

reactor using gravity
▪▪ Docking a drum onto an isolator

that is connected with the
reactor
▪▪ The reactor in this case is

located one floor below
Fig. 48 Dispensing Using Gravity
Example of Use:
▪▪ Closed filling from big bags/

FIBCs into a reactor using a
pneumatic conveyor system
Fig. 49 Dispensing Using a Pneumatic Conveyor
The introduction of solids is critical from a containment perspective.

Introduction of powder • Use of pneumatic vacuum conveyor systems
• Use of split butterfly or split cone valve systems
• Drum emptying systems using gravity
• Isolator systems or single-use technology
Cleaning • Cleaning using WIP/CIP systems
ID number:
• Avoidance of 1037317
cleaning (single-use systems)

As the materials may be compacted during storage or transport, it may be necessary to install
product crushing systems.
Containment Manual
5.2.2 Processing
In order to produce the active ingredient, the solids (starting materials, intermediates, reaction aids
such as catalysts, etc.), liquids (solvents, acids, bases, water, etc.), and/or gases must be introduced
into the reaction. The reaction process itself is carried out in reactors whilst stirring at defined
pressures and temperatures. The addition of the components can take place before or during the
reaction process.
Reactors in the chemical production of pharmaceuticals are mostly made of stainless steel, high
quality special alloys such as Hastelloy, or glass-lined.
The choice of material is made based on the substances to be used or the intended purpose.
Reactors are closed systems that may be regarded as tightly sealed during normal operation.
Exposures are thus mainly encountered when feeding the reactor with solids or at the shaft connec-
tors on the reactor such as e. g. the agitator.
Stirring Tank
▪▪ Properties: Sizes: 1 l – 20 000 l
▪▪ Materials: Glass, glass-lined, stainless steel, special

alloys
▪▪ Functions: Stirring, heating/cooling, pressure,

inerting with N2, distillation, phase separation
(extraction), transfer, …
▪▪ Use: Reactions, crystallization, reconditioning …
Picture: Glass-lined reactor with stirrer and corrosion

protection coating
In picture front right: Funnel for introducing small
amounts of solids
Reactor
▪▪ Glass-lined reactor with big bag/FIBC solid feed unit
▪▪ Big bags/FIBCs enable more efficient solid feed

than sacks or drums. Typically 200 – 400 kg/bag,
depending on bulk density
ID number: 1037317
Fig. 50 – 51 Reactors
Containment Manual
5.2.3 Solid/Liquid Separation

After the reaction, the active ingredient is often present in crystalline form in the suspension of liquid
and solids. In the next process step, the solids are separated from the liquid using filters, suction
filters, or centrifuges. The liquid is pressed through the “filter cake” under defined pressure condi-
tions using centrifugal or gravitational acceleration. The filter cake is then washed with another
liquid which is also pressed through the filter cake as previously described. At the end of the
process step the filter cake is removed.
The devices used for solid/liquid separation are closed systems which may be regarded as tightly
sealed during “normal operation”. There is a risk of exposure when removing the solids from the
apparatus, when seals fail, and at the shaft connectors.
In the following, a suction filter and a peeler centrifuge are described as an example for solid/liquid
separation. There are many other devices for solid/liquid separation.
Suction Filter
▪▪ Properties: Stirred filter device, tempered
▪▪ Sizes: 0.1 m2 to > 6 m2 filter surface area
▪▪ Materials: Stainless steel or special alloys
▪▪ Functions: Filter device for separation of solids
▪▪ Filter dryer: As suction filter, additionally the product

can be dried
Fig. 52 Suction Filter
Peeler Centrifuge
▪▪ Properties: Horizontally or vertically rotating basket

with filter cloth insert

▪▪ Functions: High rotational speed to separate solids
from liquids
▪▪ Use: Isolation of product

ID number: 1037317
Fig. 53 Peeler Centrifuge
Containment Manual
Critical steps from a containment perspective are the removal of the solids and cleaning.
Solid discharge, emptying of residual • Use of split butterfly valve systems or split cone valve
layer systems
• Glove Boxes or isolator systems or single-use technology
Cleaning • Cleaning using WIP/CIP systems
• Changing the filter cloth after pre-cleaning (rinsing)
• Changing the filter, with flexible containment as appropriate
• Use of metal filter meshes
Other notes:
▪▪ The equipment must be opened after cleaning in order to replace certain parts such as seals and
filters for a change of product or campaign. These parts must be cleansed under the permissible
thresholds before opening the equipment.
5.2.4 Drying
Before the wet substance can be further processed, in most cases it has to be dried. There are
multiple of different devices in use for drying, including e. g. tray drying cabinets for operation under
normal pressure or under vacuum, filter dryers, paddle dryers, conical dryers, and others.
The devices used for drying are closed systems which may be regarded as tightly sealed during
“normal operation”. There is a risk of exposure on introducing wet material to be dried, on removing
the dried solid from the device, on sampling, in case of seal failure, and at the shaft connections.
In the following, paddle dryer and a vacuum drying cabinet are described as examples for drying
methods.
Paddle Dryers
▪▪ Properties: Horizontal cylindrical tank with half-pipe

coils for the heating/cooling system, heated or
cooled horizontal shaft with heated or cooled stir/
mixer paddles. Dome with filter system and conden-
sation system connected to a vacuum pump.

▪▪ Functions: Filling, evacuation, heating, condensing,

cooling, sampling system and discharge into drums,
containers, or big bags/FIBCs
▪▪ Use: Drying of product
ID number: 1037317
Fig. 54 Paddle Dryer
Containment Manual
Critical steps from a containment perspective are the introduction of the wet material to be
dried, the discharge of the solid, and the cleaning.
Introduction of the wet material to be • Use of split butterfly valve systems or split cone valve systems
dried • Single-use technologies
Discharge of solids • Use of split butterfly valve systems or split cone valve systems
• Glove Boxes or isolator systems or single-use technologies
Cleaning • Cleaning with WIP/CIP systems
Other Note:
▪▪ If WIP/CIP systems are used for cleaning the device, it is theoretically possible to operate without
opening the device – this depends on the cleaning requirements.
Drying in Drying Cabinets/Tray Dryers
Drying in drying cabinets is a frequently used process step, whereby the product is generally laid
out on trays. The differentiation is made between vacuum drying and circulating air drying.
In the case of circulating air drying, the product is heated and the ensuing vapors are picked up by
the gas stream. The gas used can be inert or air. Often a portion of the air in the drying cabinet is
fed through a circulation filter and circulated by a fan.
In the case of vacuum drying, the cabinet interior is evacuated. Low temperature evaporation occurs
due to the low partial pressure. Heat transfer largely takes place through direct contact between the
foot print and the tray. The gases in the drying cabinet are fed through a vapor filter to the vacuum
pump.
If a comparison is made between vacuum dryer cabinet and a circulating air cabinet with the same
capacity, the following differences can be noted with respect to containment:
▪▪ It is easier to clean vacuum drying cabinet than a circulating air drying cabinet, because in the
latter the air ducts also have to be cleaned.
▪▪ The air filters in a circulating air drying cabinet are relatively large in comparison to the vapor
filters in a vacuum drying cabinet, which makes it difficult to exchange these in a contamina-
tion-free manner.
ID number: 1037317
Containment Manual
Critical steps from a containment perspective:
Loading and unloading the drying cabinet • Glovebox, isolator or film containment in front of the
drying cabinet door or for the trays
Cleaning the chamber: • Manually under containment conditions, or if possible
with CIP system
• Use of vacuum drying cabinets if possible due to the
better cleanability
Exchange of circulating air filters/exhaust air • BIBO exchange technique (“safe-change” filter) where
filters possible
Exchange of vapor filters • Low contamination (“safe-change” filter)
Fig. 55 – 56 Examples for the Integration of a Vacuum Drying Cabinet in an Isolator
5.2.5 Packaging
After drying, the substance (API or intermediate) is filled into containers either for transport within
the facility or for delivery.
The filling of intermediates or APIs into a container must be carried out with systems which can
comply with the occupational exposure limits (OELs) of the substance (see section 6.1 “Primary
Containment”). Weighing may take place during the filling. A sample is usually taken either during
or after the filling. Filling from the dryer can take place in a variety of manners. If there is sufficient
height below the dryer, for example, then filling may be done using gravity. If not, then filling may be
done by means of pneumatic conveyor.
A variety of systems are available for filling solids. Some examples are presented in the following
examples. Further containment systems will be shown in section 6.

ID number: 1037317
Containment Manual
Example of Use:
▪▪ Closed filling into drums or

cartons with continuous liner
using gravity.
▪▪ Product crushing
▪▪ Dosing system with scale
Fig. 57 Drum Filling with Continuous Liner
Example of Use:
▪▪ Closed weighing into drums

with a pneumatic conveyor
system
▪▪ Cone mill to crush the API

underneath the dryer before the
pneumatic conveyor
▪▪ Dosing via the pneumatic

conveyor and scales
Fig. 58 Weighing into Drums via Pneumatic Conveyor
Example of Use:
▪▪ Closed big bag/FIBC filling with

a film containment system using
gravity

ID number: 1037317
Fig. 59 Big Bag/FIBC Filling
Containment Manual
A critical step from the containment perspective is the discharge of solids.
Powder discharge • Film connection systems

• Rigid or flexible isolators
Cleaning • Cleaning with WIP/CIP systems
Other Notes:
▪▪ The construction of a filling station can be very complex, the more systems are integrated. The
transitions between each system interface can lead to a weakness in the containment, e. g. at the
shaft seals.
5.2.6 Transfer
The material must be moved between each of the individual process steps during the production of
the API. The material can be present as a solid, a liquid, a suspension, or a gas. Whereby liquids,
gases, and suspensions may be transported very readily from one device to another via tubes or
pipelines, solids may be transported via pneumatic conveyor systems (see also section 6.1.9) or in
transportable containers.
Tubes and pipelines are closed systems when they are tightly joined. In closed systems the cleaning
may be accomplished by rinsing.
In the case of containers, a differentiation is made between disposable and reusable containers.
The advantages of disposable containers include their more flexible use (one type of container for
different devices), a better control while emptying, and that there is no need for cleaning after use.
A disadvantage may be higher long-term operational costs.
Reusable containers such as drums or other transport containers, including pressure vessels, are
generally used when large amounts (volumes or weights) need to be moved. Liquids with a certain
hazard potential are transported in smaller amounts in bottles or canisters.
Smaller containers may be easily introduced into isolators or RABS for filling and emptying via ports
or airlocks. Low contamination handling of large containers when filling and emptying, e. g. with big
bags/FIBCs, is considerably more complex.
From a containment perspective, the opening and closing or filling and emptying of the containers
must be taken into account. These activities should be carried out in suitable closed systems in
accordance with the occupational exposure limits of the substance being handled (see section 6.1).

ID number: 1037317
Containment Manual

ID number: 1037317
6 Technical Systems

ID number: 1037317
ID number: 1037317
ISPE D/A/CH COP CON 6 Technical Systems
Containment Manual
6 Technical Systems
6.1 Primary Containment
6.1.1 Isolators
In terms of containment, isolators are personal protection installations with a protected possibility
for intervention in which the operator is separated from the materials being worked with by a physical
and potentially dynamic barrier. These isolators are mostly comprised of a sealed casing and
inspection windows with the possibility to handle and transfer materials e. g. using gloves.
These isolators serve to protect the operator, in contrast to the isolators in sterile production, which
primarily serve to protect the product, or other facilities which should serve both purposes.
The negative pressure in the isolator serves as a dynamic barrier as it prescribes a defined direction
of flow in case of leakage. This prevents highly potent substances being able to escape from the
isolator.
In the aseptic production with highly potent substances, protection of both product and operator
must be considered simultaneously. Whether the isolator is operated under positive or negative
pressure must be evaluated in a risk analysis.
Isolators were originally developed in the nuclear industry. This concept was adopted for the phar-
maceutical industry, because there too, substances are handled that require compliance with a
threshold value. This is not necessarily applicable to the entire production process, but rather only
for individual process steps that may not be carried out in a fully closed system. These often
include:
▪▪ Removal of substances from delivery containers,
▪▪ Weighing of substances,
▪▪ Addition of substances in the various process facilities (see section 5),
▪▪ Removal of substances from the process facilities,
▪▪ Filling/bottling of substances.
The operator must be protected during these interventions. Isolators are kept as small as possible,
in order to limit a spread of the product and avoid contamination. They are designed such that they
may be operated and cleaned in an optimal manner.
Only the parts of the machine/device that are actually required for the process are located in the
isolator e. g. product filler openings/holes. All other components of the machine/device should be
situated outside of the isolator e. g. drives/actuators. This requires an isolator design made specifi-
cally for the process. Moreover, the design of the machine/device to be integrated must often be
adjusted to meet the requirements of the isolator.
ID number: 1037317
Manual intervention is done using gloves which are built into the isolator. Older isolators also use
so-called protective “half suits“, which are built into the floor of an isolator. From an ergonomic and
hygienic perspective, these no longer reflect the state-of-the-art.
6 Technical Systems ISPE D/A/CH COP CON
Containment Manual
An isolator is made up of the following main components:
▪▪ Casing: The casing envelops the substance being handled, the process facilities/machines, and
other equipment such as e. g. media supply. The casing is generally custom-built for the specific
use case. A fundamental differentiation may be made between casing designs with flexible
material (“soft wall” isolators and single-use thin-film isolators) and those with hard material
(“hard wall” isolators).
▪▪ Windows with Gloves: The windows can be incorporated in various places on the isolator and
the gloves can be positioned according to the ergonomic and process related requirements of the
operator. The final positioning is determined in an ergonomic study (mockup).
▪▪ Ventilation System: The ventilation system controls the internal pressure. Depending on the
process, isolators may comprise any number of chambers. Each chamber may have its own
pressure and ventilation concept, depending on the process requirements. Air intake filters
ensure the required purity of the inbound air, and air outlet filters ensure that exhaust air is suffi-
ciently cleaned. It must be possible to change the filters without contaminating the isolator
surroundings. Various systems are available to achieve this, including e. g. “push-push” filter
exchange systems or “bag-in bag-out” exchange systems (see section 6.3).
▪▪ Cleaning System: Optionally manual or automatic WIP/CIP (see section 8.4.1.4).
Depending on the case, the following systems may also be used:
▪▪ Inerting: Rinsing the isolator with an inert gas (mainly N2).
▪▪ Air Conditioning: Controlling the temperature and humidity in the isolator.
▪▪ Biodecontamination: Cold process for decontaminating the surfaces in the isolator with gaseous
hydrogen peroxide preferred for the reduction of microbiological impurities.
Transfer systems are important components of an isolator. These are required for introducing and
removing substances, tools, packaging, waste, and other materials. Transfer systems used with
isolators include e. g.:
▪▪ Rapid Transfer Ports (see section 6.1.4),
▪▪ Split butterfly valve systems (section 6.1.5),
▪▪ Split cone valve systems (section 6.1.6),
▪▪ Film connection systems (section 6.1.7),
▪▪ Single-use technologies (section 6.1.11),

▪▪ Material airlocks (section 6.2.7),
▪▪ Bag-in Bag-out systems (section 6.3).

ID number: 1037317
Containment Manual
Fig. 60 Example of an Isolator
Fig. 61 Another
This Document is licensed to example of an isolator
6.1.1.1 Ergonomic Study (Mock-Up)

It is difficult to adjustBelo
a finished isolator made of Minas
Horizonte, stainless steel and glass, and it is necessary,
Gerais,
therefore, to carry out a so-called mockup. In the mockup the overall isolator geometry is decided
ID number:
on based on a model. All processes 1037317
and manual steps are tested on the mockup model by the
operators e. g. the position of the gloves, the operability of the machines, the cleaning, and the
material transfers.
Containment Manual
Fig. 62 Example of a
Mockup Study
6.1.2 Systems with Low-Turbulence Displacement Flow (Laminar Flow Systems)

The differentiation is made between turbulent and laminar flow types. As the ideal state of a laminar
flow is almost never attained in the pharmaceutical industry, mention is instead made of low-
turbulence displacement flow. Low-turbulence displacement flow may be directed vertically or
horizontally.
In the case of low-turbulence flow, the air moves evenly and ordered in parallel layers. The indi-
vidual layers do not mix and thus particles may be picked up and transported away.
In the industry, vertical flow is generally used because this is a stable flow type and the air quality
is independent of the point of observation. A further advantage of vertical displacement flow, is that
gravity acts in the direction of flow. In practice, there are disturbances caused by the operators,
tools/machines, and product containers.
These systems are often used in booths for weighing or sampling. They serve primarily to protect
the people working in them. In addition, contaminated air is removed by a defined exhaust air flow.
Such booths are also known as laminar flow or downflow booths.

Design and Operating Principle:
The general design and simple operating principle of this system is shown in Fig. 63. The passage
of air is shown schematically with arrows.
Once the air has passed through the perforated grid of the intake duct, it then flows through the
ID number:
prefilter and then a secondary 1037317
filter e. g. a particulate and/or activated carbon filter. The pre-cleaned
air is then led along the rear panel through the system and fed back by means of a ventilator.
Depending on the application, the air may be conditioned.
Before the air can be deployed in the form of a clean air stream, it must pass through the air intake
filter, a particulate filter, in order to ensure airborne particulate cleanliness. The clean air is then
passed back into the booth. It is evenly distributed as a vertical, low-turbulence displacement flow
Containment Manual
throughout the entire cross-section by means of a laminator. In the case of critical substances,
ventilating systems using solely fresh air are preferred.
In addition, laminar flow systems generally also have transparent antistatic PVC curtains which
serve as operating area boundaries.
Fig. 63 Schematic of a “Laminar

Flow” System
Characteristics of the Systems:
Limited personal protection for handling highly Product may be spread along personnel and
potent substances material pathways
Processes with low protection requirements Products with low OEL thresholds may not be
handled
Simple cleaning is possible thanks to the surface The focus is on product protection
contours
Universally applicable for many use cases

6.1.3 Restricted Access Barrier System (RABS)
The term RABS refers literally to a barrier system with limited access. It is a system with limiting
physical barriers between the operator and the production area.
A fundamental differentiation is made between passive RABS and active RABS. In the case of
passive RABS, the air supply ID number:
is taken 1037317
from the installation area (the cleanroom). In the case of
active RABS, there is a further intermediary air treatment unit equipped with HEPA filters which
filters the inlet air supply and then feeds it in to the workspace.
The flow of air in the different RABS types is depicted in the following diagrams:
Containment Manual
Fig. 64 Passive Open RABS (oRABS) Fig. 65 Active Open RABS (oRABS)
Process interventions are effected using gloves. In the case of both active and passive RABS, air
flows out of the cleaner area into the less clean area and is then sucked in by the room ventilation
system and fed back into the production area.
These systems fulfil the following prerequisites:
▪▪ Protection of a product being processed from other products and impurities,
▪▪ Aseptic environment in the interior space.
In addition to active and passive open RABS, it has been noted in the last few years that cRABS
(closed RABS) is being increasingly used. cRABS is a closed system in which the return air is fed
back internally, exactly as in isolator technology. Here too, a differentiation is made between passive
and active cRABS.

Fig. 66 Closed RABS (cRABS), left with double
ID number: 1037317
panes for return air, right depiction with filter in
front of return air for processing highly potent
substances
cRABS is operated with circulated air this. Air circulates internally; only a small proportion of air is
sucked out of the installation room in order to maintain negative pressure within the cRABS.
Containment Manual
Fig. 67 RABS Performance

Level: This diagram shows
which protection targets can
be achieved with RABS and
isolators
6.1.4 Rapid Transfer Ports (RTP)

RTP technology makes it possible to pass materials in and out of a closed system without having to
carry out decontamination. The double door technology was developed for the nuclear industry and
permits rapid introduction and removal processes without injuring the containment.
RTP technology can be used in many different applications for handling highly potent substances
in the pharmaceutical and API industry.
Fig. 68 Alpha Port on a Softwall Weighing Isolator
RTPs can be used for OELs down to < 1 µg/m3.
A RTP is made up of two independent units. The locking unit preferably mounted on a containment
in a fixed manner is designated the “alpha port “, whereas the universally deployable mobile unit is
called the “beta port”. When combined or docked, the two units form a closed system.
Beloagain
Both units can be separated Horizonte, Minas
from one another
ations to introduce or remove material.
Gerais,
and thus permit any number of transfer oper-
ID number: 1037317
The fundamental principle of the RTP technology is based on both units forming a high containment
area independent of one another. The joining up and separation of both units is resolved mechani-
cally such that a leakage never occurs and the containment cannot be broken.
Containment Manual
Beta Port
Alpha Port Fig. 69 Alpha and Beta Ports
Multiple mechanical locking systems prevent operating errors and thus unintentional opening of the
contaminated area.
Schematic Diagram and Examples to Clearly Illustrate the Operating Principle:
inside the inside the

equipment turning equipment
transfer in both directions
Beta Port
open up
Alpha Port
outside the outside the
equipment equipment
Fig. 70 a The alpha port of a Fig. 70 b The beta port is Fig. 70 c Opening the alpha
containment is joined with the joined and tightly sealed with port lid automatically opens
matching beta port (e. g. a the alpha port by turning. the beta port lid and transfer in
transport container) Turning simultaneously opens either direction can be
the beta port lid and joins it effected. This procedure is
with the alpha port lock reversible and can be repeated
indefinitely
Fig. 71 Beta Port with

Lid on a Transport
Container Fig. 72 Alpha Port

IDFig. 73
number: Alpha 1037317 Fig. 74 Alpha Port
Port and Closure Closure with Docked
Unit with Locking Beta Port Lid and Trans-
Mechanism port Container
Containment Manual
RTP System Characteristics:
Protection of product and personnel even when handling High demands on personnel with respect to
highly potent substances handling the RTP
Very high containment possible (OEL ≤ 1 μg/m³) Little or no possibility to automate
Both unit parts are always in a closed system, even Diverse parts such as seals, locking mecha-
when they are not joined nisms, and hinges require maintenance
Systems are available in different materials (plastics,

stainless steel)
Universally applicable for many use purposes
Other Notes:
▪▪ When separating the alpha and beta ports, the external surface of the seal between the touch
points can be contaminated with substance. From experience, this so-called “ring of concern” is
only very slightly contaminated. Any risk for the workers is product-dependent and should be
evaluated accordingly.
Areas of Application (Examples)
▪▪ Tablet Press Containment
Fig. 75 Transfer Container on a Tablet Press
▪▪ Weighing Isolator

Fig. 76 Waste Port with
Continuous Liner on a Weighing
ID number: 1037317
Isolator
Containment Manual
6.1.5 Split Butterfly Valve Systems

Split butterfly valve systems make it possible to carry out dust-free filling and discharging (depending
on the system, down to OEL ≤ 1 μg/m³) of bulk materials, while at the same time protecting operator
and environment from contamination by the product.
Split butterfly valve systems are used in particular for handling highly potent substances and in
challenging applications in the pharmaceutical and API industry.
Fig. 77 Charging a Conical Mixer
The fundamental principle of split butterfly valve systems, is the combination of two separate halves
of a flap disk which are only joined/docked with each other during filling or emptying. While sepa-
rated from each other, containers, receptacles, or downpipes are closed by one of the flap disk
halves. This ensures that the process is always closed.
For filling or emptying at a filling or discharge station, the container with the passive valve is
connected to the filling or discharge station with the active valve. The passive and active valves
must be designed such that they form a self-contained unit when docked.
There are different variants of split butterfly valve technologies depending on the manufacturer,
ranging from horizontally arranged flap disks to tilted or inclined designs. There are also additional
options which make it possible to clean between the flap disk halves before undocking. Docking the
passive and active valves can be automatic or manual.

ID number: 1037317
Fig. 78 a Active valve of a Fig. 78 b The active and Fig. 78 c The rotary drive
split butterfly valve system passive valves are firmly opens both docked flap disk
with drive and two locking pins docked halves of the active and
for centering and positioning passive units thus enabling
the passive valve closed-system filling or
emptying
Containment Manual
Characteristics of the split butterfly valve system:
Protection of product and personnel even when handling Low demands on skills of the personnel
highly potent substances
Very high containment possible (OEL ≤ 1 μg/m3) High degree of automation possibilities
Automated cleaning equipment (CIP/WIP) Possibility of product migration in seals and

shaft through-holes
Systems may be used with flexible packages and Wear and tear may lead to a containment risk
containers
Primary containment system
Other Notes:
▪▪ Split butterfly valve systems have wearing parts which must be subjected to regular maintenance
and visual inspections.
▪▪ Very precise manufacturing methods are required to make split butterfly valve systems.
▪▪ When separating split butterfly valve systems, the external surface of the seal and the flap disk
halves can be contaminated with substance. From experience, this so-called “ring of concern” is
only very slightly contaminated. Any risk for the operators is product-dependent and should be
evaluated accordingly.
Areas of Application (Example):
▪▪ Product transfer in a mobile transport container/IBC

Fig. 79 Closed
Belo Horizonte, Filling of Container
Minas Gerais, Using Split Butterfly
Valve System
ID number: 1037317
Containment Manual
6.1.6 Split Cone Systems

Split cone systems make it possible to carry out dust-free filling and discharging (depending on the
system, down to OEL ≤ 10 μg/m³) of bulk materials, while at the same time protecting operator and
environment from contamination by the product.
Split cone systems are used in particular for handling highly potent substances and in challenging
applications in pharmaceutical and API manufacturing.
The fundamental principle of split cone systems, is that these are comprised of two separate halves
of a cone (active and passive cones) which are joined/docked with each other during filling or
emptying. While separated from each other, containers, receptacles, or downpipes are closed by
one of the cone halves, thus ensuring product transfers in a closed system.
For filling or emptying, the passive cone part on the container is docked onto the active cone on the
filling or discharge station. The passive and active cones must be designed such that they form a self-
contained unit when docked. Docking the passive and active cone halves can be automatic or manual.
The following diagram illustrates the operating principle.
Fig. 80 a The container Fig. 80 b Active and Fig. 80 c On closing, the
with passive cone is posi- passive cones are tightly. active cone moves back to
tioned above the active To open the system, the the starting position and
cone using a lifting unit active cone moves into the the passive cone closes
container the container
Characteristics of Split Cone Systems:

Mr. Bruno Henrique Santiago

Protection of product and personnel even when handling
Low demandsLima on skills of the personnel to
highly potent substances operate the system
High containment possible (OEL ≤ 10 μg/m )
3
High degree of automation possibilities
ID number:
Automated cleaning equipment (CIP/WIP)
1037317
Possibility of product migration in seals and
shaft through-holes
Systems may be used with flexible packages and
Wear and tear may lead to a containment
containers risk
Containment Manual
Other Notes:
▪▪ Split cone systems have wearing parts which must be subjected to regular maintenance and
visual inspections.
▪▪ Very precise manufacturing methods are required to make split cone systems.
▪▪ When separating the active and passive cones, the external surface between the touch points
can be contaminated with substance. From experience, this so-called “ring of concern” is only
very slightly contaminated. Any risk for the operators is product-dependent and should be evalu-
ated accordingly.
▪▪ Container Discharge
Fig. 81 Discharge of a Tablet Container/IBC with Split Cone System
6.1.7 Film Connection Systems

Film connection systems make it possible to carry out dust-free filling and discharging (depending
on the system, down to OEL ≤ 1 μg/m³) from any containers with inliners. Both operators and the
environment are protected from contamination by the product. The high containment level is
achieved through the use of protective films, even when changing containers. Film connection
systems are used in particular when handling highly potent substances and for special applications
in pharmaceutical and API manufacturing.

ID number: 1037317
Fig. 82 a Closed-System Charging of a
Reactor from a Big Bag/FIBC
Containment Manual
Film connection systems are single-use systems characterized by the filling and discharge of
product under closed-system conditions using protective film.
For filling or discharging, a film bag/inliner is attached over the top of a product inlet tube which is
closed with a protective film using the double O-ring technology (Fig. 82b). Following this, another
film bag/inliner is attached analogously to the lateral access port (Fig. 82c), which can then be used
to remove the protective film from the product inlet tube under contamination-free conditions
(Fig. 82d). The protective film can be discarded in the lateral film bag (Fig. 82e). After removing the
protective film, the product can be safely transferred from the respective container (Fig. 82f). The
film bag/liner can be separated from the system using a suitable sealing system (Fig. 82g).
b) c) d)
e) f) g)
Fig. 82 b – g Operating principle of film connection systems
Characteristics of Film Connection Systems:
Suitable for: To Note:
Protection of product and personnel even when handling High demands on skills of the personnel to
highly potent substances operate the system
Very high containment possible (OEL ≤ 1 μg/m³) Limited/no possibility of automation

System is closed at all times, even when no container is
attached (residual film on the inlet tube)
Possibility of product propagation in ventila-
tion or external filters
Automated cleaning equipment (CIP/WIP)

Systems may be used for many flexible containers with
inliners
ID number: 1037317
Containment Manual
▪▪ Film Connection System for Big Bag/FIBC Filling at a Centrifuge
Fig. 83 Centrifuge Discharge into a Big Bag/FIBC
6.1.8 Sampling, Samplers

Frequently in the production of oral solid dosage forms, samples of the product must be taken along
the complete process (in-process controls). These samples serve to ensure compliance with the
stipulated cGMP guidelines and are, ultimately, indispensable in protecting patients.
The following diagram provides an example of various samplings taken in a typical production
process for film-coated tablets.
Production of a Film-Coated Tablet
API Production Sampling
Tablet Production
Sampling
Incoming Goods Samples e.g. from Process Step
• Weighing
• Mixing – Sieving
• Granulation
Tablet Production
Sampling • Drying
In-Process Control
• Milling
• Blending
• Tableting
Tablet Production
Quality Control
Sampling
• Coating

Sampling from a Production Process for Film-Coated Tablets

If in-process controls are executed in the production with highly potent substances, appropriate
IDtonumber:
technical measures must be taken 1037317
protect the operator of the manufacturing equipment from any
hazards arising from the product.
Containment Manual
As a matter of principle, all process steps, including the sampling and in-process controls, must be
taken into consideration during the design and construction phase of the equipment and verified
during mockup. Examples of technical measures are summarized in the following table.
API Production Isolators, single-use sampling systems, manual or automated

integrated samplers
Tablet Production Isolators, single-use sampling systems
• Incoming Goods
Tablet Production In-Process Control Isolators (weighing usually takes place in an isolator)
• Weighing
Tablet Production In-Process Control Single-use sampling systems, manual or automated integrated
• Mixing – Sieving samplers, PAT/NIR*
Tablet Production In-Process Control Manual or automated integrated samplers, PAT/NIR*
• Granulation
Tablet Production In-Process Control Manual or automated integrated samplers, PAT/NIR*
• Drying
Tablet Production In-Process Control Isolators (if the milling takes place in an isolator), manual or
• Milling automated integrated samplers, PAT/NIR*
Tablet Production In-Process Control Isolators (if tableting takes place in an isolator), manual or
• Tableting automated integrated samplers, integrated washable tablet
testing system
Tablet Production In-Process Control Manual or automatic integrated samplers
• Coating
Tablet Production Isolators, single-use sampling systems

• Quality Control
*PAT/NIR = Process Analytical Technology/Near Infrared Spectroscopy
The sampling points must be taken into consideration during the occupational hygiene validation of
the containment. If an OEL measurement is performed, then it is recommended to include the
sampling process step.
Other Notes:
As the product samples must later be removed from the sample container at the place of analysis
(e. g. the laboratory), the entire process chain including all process steps must be checked with
regard to containment measures and their application.
6.1.9 Pneumatic Conveyor Systems
As the product samples must later be removed from the sample container at the place of analysis
(e. g. the laboratory), the entire process chain including all process steps must be checked with
regard to containment measures and their application.
ID number: 1037317
Containment Manual
Fig. 84 Pneumatic

Conveyor System for
Filling a Reactor from
Big Bags/FIBCs
Operating Principle
Negative pressure is generated in a feeding point or container by a vacuum pump connected via a
pipe or tubes and product sucked in. In order to maintain the vacuum, the system is operated closed
off from the outside. The product-gas mix flows through a product inlet valve and into the separating
chamber of the vacuum conveyor equipment. Depending on the system, the transfer can be realized
with a lean or dense phase transfer in order to minimize the mechanical impact onto the product.
The fine dust particles are removed by a filter integrated within the system and the product-gas mix
is thus separated again.
The suction cycle ends when the separating chamber is filled with product. The discharge into the
connected system can begin. The product outlet valve is opened and instead of a negative pres-
sure, the direction of gas flow is reversed by means of compressed air (or nitrogen). Any fine
components attached to the filter are cleaned off so that the filter is cleansed ready for the next
suction cycle. Thresholds of OEL ≤ 1µg/m3 can be achieved with pneumatic conveyor systems.
The following diagrams illustrate the operating principle of pneumatic conveyor systems:

Fig.85 a In the starting position
Belo Fig. 85 b The
Horizonte, product Gerais,
Minas Fig. 85 c To discharge,
all valves are closed. The inlet valve is opened and the direction of gas flow
vacuum pump generates nega-ID number: 1037317
the product is sucked in to is reversed. At the same
tive pressure in the pneumatic the system by the negative time, the filter medium is
conveyor and tubing pressure and fills it cleansed again. Then the
Downloaded on: 1/15/19 11:37 AM next transfer cycle can
begin
Containment Manual
Characteristics of Pneumatic Conveyor Systems:
Containment system for transferring powders Execution of filter replacement and cleaning. Check
and granulates in the API field whether it is possible to clean the filter before removal,
or whether it can be removed using technical measures
such that the required OELs can be complied with
Pneumatic conveyor systems are suitable for Hygienic design of the filter and filter installation. The
various process connections and can thus filter should be installed such that product propagation
help to reduce or avoid containment inter- into the seals and filter support can be eliminated
faces
Pneumatic conveyor systems can also be A WIP (Washing in Place) of the pneumatic conveyor
used where there is limited space or if system should be considered during the equipment
charging or discharging using gravity is not design
possible
Other Notes:
In addition to the pneumatic vacuum conveyor systems already mentioned, pneumatic pressure
conveyor systems are also used in the industry. Pneumatic pressure conveyor systems require
particular attention with regard to system tightness within the framework of containment and are
seldom used in this area.
▪▪ Tablet Press
Fig. 86 Pneumatic vacuum conveyor system

This Document is licensed to for loading a tablet press
6.1.10 Other Connections

In addition to the classic Horizonte,
Belo containment connections
Minas such asGerais,
split butterfly valve systems or split cone
systems, there are also other connections that should be considered. Among these are the
so-called quick connectionsIDwhich
number:
may be used1037317
to decouple a weighing scale, or between two fixed
systems. Other connections run from inside to outside via shaft through-holes. All these systems
are admittedly closed at first glance, but they may carry a risk of becoming inefficient containment
due to incorrect installation, wear and tear, or faulty design.
Containment Manual
Quick Connections
Quick connections, also known as tri-clamp or camlock connections, are widely used in pharmaceu-
tical production and provide a simple possibility to connect and disconnect processes and connec-
tion systems.
A tri-clamp connection with a flexible intermediate section, as shown in Fig. 87, is comprised of the
tri-clamp connection pieces/ferrules, a gasket or flexible intermediate section, and a clamp to close
the connection. In these systems, attention must be paid to correctly fit the gasket between the two
ferrules. Both soft and rigid gaskets may be used. The softer the gasket, the more difficult it is to
position it correctly. In the case of rigid gasket materials, there is a risk of leakage. In addition, rigid
gaskets do exist with a soft core, which allows them to be correctly fitted more easily. There are two
variants of fastening clamp design which, depending on the application type may be closed manually
or with a tool. In the case of both variants, it must be ensured that the tightness of the connection
and thus compliance of the containment is reproducibly given.
Fig. 87 Tri-Clamp Connections
Flexible Connections
Flexible connections, such as e. g. compensators, sleeves, etc., are used for example for decoupling
weighing scales or rigid systems. In practice, the fastening of flexible connections can lead to a
containment risk.
As illustrated in the Fig. 88, a flexible sleeve is fastened using so-called tensioning straps. The
handling and secure closure of the tensioning strap presents a possible weakness for this type of
connection.

ID number: 1037317
Fig. 88 Flexible Decoupling
Containment Manual
Shaft Through-Holes
Shaft through-holes are built into many systems and equipments such as e. g. a dosing unit. There
are a multitude of different sealing possibilities for these shaft through-holes. Due to their complexity,
it is not possible to go into details in this chapter.
It should be noted that all these different types of seals are naturally subject to wear and tear due
to the nature of their design and usage. The necessary visual inspections, routine maintenance
measures, and also possible product propagation in the seals and shaft through-holes must be
considered in a risk evaluation.
6.1.11 Single-Use Technologies

Flexible single-use technologies are used particularly in areas where the product is changed
frequently e. g. in Analytics, in Research and Development, and for maintenance work.
Flexible single-use technologies are not fixed installed systems, but are used rather for short-term
activities and subsequently disposed of in a safe and correct manner.
They may also be used as packaging systems such as e. g. film bags inside drums.
Fig. 89 Disposable Isolator for Weighing and

Dispensing
6.1.11.1 Disposable Isolators
Description:
Disposable isolators, such as e. g. film isolators, are set up similarly to stainless steel isolators. The
workspace of a flexible disposable isolator, in contrast to that of a stainless steel isolator, is envel-
oped within a flexible film. This film can be made from LDPE (low-density polyethylene), PU (poly-
urethane), or from other film materials. In practice, the use of LDPE and PU has established itself.
The advantage of LDPE film is that it may be readily welded with other polyethylene components
such as e. g. connection ports, whereby the proportion of disposable parts is then increased. All
disposable isolators require a rigid framework or support on which to securely fix the film and
connection ports.
ID number: 1037317
Containment Manual
In addition to film isolators, flexible bags and continuous liner systems can be used for transferring
pharmaceutical material in and out of the equipment, or for closed filling of pharmaceutical products
into drums or cartons. Thresholds down to OEL ≤ 1µg/m3 can be achieved with single-use tech
nologies.
Flexible isolators are suitable for weighing, Test for leakage before use. The containment level to
product sampling, attachment to process be achieved is dependent on the design of the
systems, protective systems for changing attached parts such as e. g. airlocks and connection
filters, or for maintenance and cleaning work ports
If the films are to be glued on a rigid part, special
attention must be paid to the tightness of the glued
areas
Other Notes:
Depending on the application and the product used, flexible isolators may be used over a longer
period of time. Regular visual inspections and functional tests must be laid out for the disposable
system within the framework of the risk analysis.
▪▪ Coater
Fig. 90 Disposable Isolator attached to a Labora-

tory Coater for Filling and Discharging Tablets

ID number: 1037317
Containment Manual
6.1.11.2 Continuous Liner Systems
The following schematic illustration of the continuous liner technology explains the operating principle:
Fig. 91 a Starter position: Fig. 91 b Liner is pulled into Fig. 91 c Liner is closed two
Liner is mounted on endless the bin. Liner is filled with times by a containment clip.
liner filling head. The shower product Due to the two clips and the
cap of the liner is closed by a separation between the clips,
containment clip you can secure a closed
system. Different clips are
available
Characteristics of the System:
Continuous liner The film liners are folded either vertically or horizontally. When folding, it must
systems are suitable be ensured that the film is not damaged. The film sealing system is of impor-
for transferring tance for continuous liner systems and numerous systems exist. The system
product and material must not damage the film during the sealing process. The film closure must be
and for closed filling firmly attached so that it may not detach itself from the film. Closures should be
into drums and set close to one another and subsequently separated in the middle
cartons
6.1.11.3 Film Closure Systems
Film closure systems are used with film isolators (section 6.1.11.1), continuous liner systems (section
6.1.11.2), and with the film connection systems described in section 6.1.7. A differentiation is made
between mechanical and thermal film closure systems.

ID number: 1037317
Containment Manual
Mechanical Film Closure Systems
As a rule, mechanical closure systems consist of two closure crimps which are fastened flush with
one another in a ring-like fashion around the section of film to be separated. The closure crimps are
comprised either of two separate crimps or of one double crimp. The double crimp has the advan-
tage that the distance between the two crimps is reduced to a minimum. A film cutter is used to cut
the film between the closure crimps.
The operating principle of a mechanical closure system with a double crimp and separate cutting
device is shown in Fig. 92.
Fig. 92 Attaching, Sealing, and Cutting the Double Crimp
Function Type To Note
Film closure system with • If a crimp is loosened during separation a containment breach may result.
double crimp (preset • The points of separation at both film ends should be sealed with adhesive
distance between the tape
points of separation • Variants of the double crimp also exist with crimp locks. The crimp locks
determined by the tech- are firmly attached to the crimp halves. After the crimps have been sepa-
nology) rated from one another, the crimps and film ends are locked with the crimp
locks
Film closure system with • In this system, the crimps are attached to the film one after the other. The
single crimps distance between the crimps is determined by the operator. If the distance
is too big then this could lead to a containment risk if the film should unfold
and release particles
• The points of separation at both film ends should be sealed with adhesive
tape
Other Notes:
All film closure systems entail the risk that the film closure can damage the primary packaging
material during transport.

ID number: 1037317
Containment Manual
Thermal Film Closure Systems
As a rule, a thermal film closure system comprises two film welding jaws. Ideally, the two welding
jaws will produce a threefold welding seam.
A threefold welding seam simultaneously results in the closure of the filled film bag and the bottom
of the new film bag. The middle welding seam may be wider and equipped with an automatic sepa-
ration of the film in the middle of the welding seam. This reduces the contamination risk.
The design of the film welding device with regard to temperature or welding process depends on
the material to be welded.
Fig. 93 Film Welding Device Attached to a Continuous Liner Port

for Discharging Product
Function Type To Note
Thermal film closure • Malfunctions can occur at the weld seam if the film is not correctly tensioned
system with separate and folds in the film lie on top of one another
weld jaws • Substance residues on and in the welding seam can also lead to a malfunction
of the weld seam
6.1.12 Local Extraction Ventilation

Dusts, aerosols, gases, and/or vapors are released into the room air in virtually every production
process dealing with APIs and their dosage forms. Local extraction ventilations are a common
method to eliminate these foreign particles, which for simplification will be referred to as particles in
the following. The particles resulting from a process are aspirated in as completely as possible, with
as little room air as possible, fed into a separator and then - separated from the air - discharged.
The aspiration, or better, the collection of particles is examined more closely in the following.
Belo
Just how important the Horizonte,
collection is in the Minas Gerais,
disposal of particles can be seen in the quantitative
balance from the VDMA Guide “Erfassen luftfremder Stoffe” (Collecting Foreign Materials from Air)
shown in Fig. 94: a goodID number:
degree of separation1037317
from filters is ineffective if the particles cannot be
sufficiently captured.
Containment Manual
Fig. 94 Quantitative Balance (Schematic Based

on the VDMA Guide “Erfassen luftfremder
Stoffe” [Collecting Foreign Materials from Air])
The objectives of collection are:
▪▪ Particle removal as completely as possible (without contaminating the workroom),
▪▪ The lowest possible level of impurities (equipment remains clean),
▪▪ The lowest possible interference in the production process.
As can be seen in the comparison in Table 1, differentiations are made between:
System Advantages Disadvantages
• No risk of particle distribution • Deposits are formed within the

in the working room enclosure
• Demands on air amounts are • The enclosure makes it more
low difficult to remove these
deposits
• The enclosure makes it more
difficult to access the process
Fig. 95 Closed System, Particle

Source Enclosed
• When correctly designed, low • Deposits are formed inside the
risk of particle distribution in booth
the working room
• Accessibility depending on the
• Relatively high demands on air
amounts
height and breadth of the • Accessibility depending on the
booth height and breadth of the
Mr. Bruno Henrique Santiago Lima booth

Fig. 96 Half-Open System, Inlet
Air Booth ID number: 1037317
Containment Manual
System Advantages Disadvantages
• Low effort and low spatial • Even when correctly designed

requirements there is a risk of a propor-
• Low interference in the produc- tionate particle distribution in
tion process the working room
• When correctly designed,
hardly any deposits
Fig. 97 Open System, Nozzle
Tab. 1 Comparison of Collection Types with Schematics Based on the VDMA Guide “Erfassen
luftfremder Stoffe” (Collecting Foreign Materials from Air)
Aspiration in Closed Systems
A casing (e. g. isolator, see section 6.1.1) seals off the particle source from the working room. A
defined volume flow is aspirated through an exhaust air outlet creating negative pressure in the
casing. Inflowing air comes in preferentially through selective openings at suitable points. Often,
however, exchange of materials and/or moved components lead to recesses in the casing. The
room air should have a defined inlet flow speed, and thus the “leakages” on the casing are decisive
for the volume flow required.
Aspiration in Half-Open Systems
Half-open systems are booths (e. g. laminar-flow systems, see section 6.1.2) which channel a
laminar airflow and make the process readily accessible from the air intake side. The volume of
air flow required is higher than for closed systems, because the inlet air velocity must take into
consideration the entire cross-sectional area of the booth.
Aspiration in Open Systems
Open systems pick up the particles directly at the source by placing suction nozzles there as closely
as possible. In contrast to collections with casings, the particles are instantly accelerated to trans-
port velocity, which in turn keeps the area around the particle source relatively clean.
Examples of closed systems are isolators (see section 6.1.1), examples of half-open systems are
laminar flow systems (see section 6.1.2), and see Figures 98 and 99 for examples of open systems.
ID number: 1037317
Fig. 98 – 99 Examples of Local Suction Extractions
Containment Manual
6.1.13 Safety Cabinets

A safety cabinet should protect the operator and environment – in the case of some types of safety
cabinets also the product – from detrimental suspended particles which may be produced during the
process step. It cannot ensure the retention of gases. Safety cabinets may be used in the following
areas of application
▪▪ Biological agents up to risk group 3 (also permissible for risk group 4 when operated with full
protection suits with external air supply and appropriate equipment for the laboratory and safety
cabinet),
▪▪ Genetically modified agents up to risk group 3 (also permissible for risk group 4 when operated
with full protection suits with external air supply and appropriate equipment for the laboratory and
safety cabinet),
▪▪ Hazardous materials e. g. cytostatic drugs or other CMR substances.
The classification of safety cabinets classes 1 – 3 is not associated with the four risk groups of the
biological or genetically modified agents.
The different classes of cabinets are explained in the following.
Microbiological Safety Cabinets Class 1
Microbiological safety cabinet (MSC) of class 1 is a modified fume cupboard in which the exhaust
air is cleansed by at least one high-efficiency particulate air (HEPA) filter. The operator is thus
protected, but sterile work with biological material is not possible because contaminated air from the
laboratory is sucked into the workspace in the cabinet.

Fig. 100 MSW Class 1
ID number: 1037317
In a class 2 MSC there is a work access opening at the front. Protection of both personnel and
product is effected by means of an air barrier.
Inside the working space there is a vertical low-turbulence displacement stream of air which has
been cleaned through a HEPA filter. This reduces the propagation of contaminations within the
Containment Manual
working space of the cabinet. Exhaust air is cleansed through at least one HEPA filter to prevent
airborne particulates from exiting.
There is also a special form of safety cabinet for cytostatic substances in accordance with
DIN 12980. In addition to the characteristics described above, this also ensures low-contamination
filter changes, since as a rule, cytostatic substances cannot be decontaminated. This is generally
achieved by an additional filter stage in a modular design.

Fig. 102 Safety Cabinet for Cytostatic Substances

A class 3 MSC provides a closed space for performing experiments with at least one suitable
IDair number:
material airlock. Inside, the pressure is lower1037317
than the surroundings. The inlet air is cleansed with
a HEPA filter and passed to the outside with a dedicated exhaust air system. Work inside the
cabinet can only be carried out using airtight arm length gloves or manipulators.
Containment Manual
Protective Functions:
▪▪ Retention Capability (Protection of Personnel)
Retention capability is the ability of a barrier to hold back aerosols. Safety cabinets achieve this
through the tightness of the casing, the secure fitting and leak-free operation of the HEPA filter,
and where appropriate, through the flow conditions at the work access opening.
▪▪ Protection of Product
This is achieved by preventing particulates from the surroundings from entering into the work-
space.
▪▪ Protection Against Propagation
Protection against cross-contamination: The capability of a MSC to prevent the direct or indirect
transfer from one substance to another within the workspace.
MSW Characteristics
MSC Class 1 Only ensures the retention capability
MSC Class 2 Ensures the retention capability, product protection, and protection against propa-
gation (prevents cross-contamination)
Safety cabinets Low-contamination change of filter
for cytostatic
substances
(additionally) Mr. Bruno Henrique Santiago Lima
MSC Class 3 Belo
Ensures Horizonte,
the retention capabilityMinas Gerais,
ID number: 1037317
Containment Manual
6.2 Secondary Containment
6.2.1 Workspaces/Ventilation/Airlock Systems

The term secondary containment refers to protective measures for personnel and the environment
set up around the primary containment (see section 6.1).
In the case of incidents during maintenance and repair, and due to operating errors, it cannot be
ruled out that highly potent substances escape from the primary containment into the surrounding
rooms. The objective of the secondary containment is to prevent a further propagation of highly
potent substances into the surroundings.
In order to achieve this, special requirements are made on the workspace concept with regard to
flow of material, flow of personnel, room layout, ventilation, pressure cascades, and airlocks. These
are discussed in the following.
6.2.2 Workspace Concept

The workspace concept must be designed according to the potential hazard and should be defined
based on a risk analysis.
It should be noted that some regulations demand dedicated areas for certain highly potent
substances. In such cases separate room groups must be established for each individual substance;
the primary protective systems (see section 6.1) must be used in a dedicated manner.
Important aspects in elaborating the workspace concept include:
▪▪ Toxicity of the substance,
▪▪ Probability of escape of the substance,
▪▪ Propagation potential/propagation routes of the substance,
▪▪ Collectability and cleanability of the substance,
▪▪ Propagation hazard posed by contaminated personnel leaving the room,
▪▪ Secure and complete cleaning, removal of contaminated containers, equipment, cleaning utensils,
and waste via airlocks without risk of contamination or propagation,
▪▪ Accessibility of all contaminated areas for cleaning,

▪▪ Sufficient space for working with personal protective equipment (PPE),
▪▪ Breathable air supply for PPE,

▪▪ Free escape routes.
ID number: 1037317
Containment Manual
Taking the above points into consideration, the following concepts should be elaborated from the
perspective of protection of personnel and the environment:
▪▪ Material flow concept,
▪▪ Personnel flow concept,
▪▪ Emergency concept (inclusion of emergency services!),
▪▪ Dismantling concept (how can the equipment be dismantled without contamination or propaga-
tion of the substance?),
▪▪ Repair and maintenance concept,
▪▪ Decontamination concept,
▪▪ Waste disposal concept,
▪▪ Emergency stop concept in case of an incident,
▪▪ Additional space requirements for PPE and devices for decontamination.
In the following, some workspace concepts are presented together with their advantages and limi-
tations (from the perspective of protection of personnel and the environment).
6.2.2.1 Workspace without Airlocks

Arbeitsraum
für hochaktive
Substanzen
Direction of flow of personnel

Direction of flow of material
Workspace for
highly potent
substances
Fig. 104 Workspace without Airlocks
Advantages To be observed
Low costs High risk of propagation of escaped substances into the surroundings

Simple to realize
Low space requirement

Overlap of material and personnel pathways
Contaminated material containers in the workspace (thus potential contamina-

tion of the cleanroom)
Mr. Bruno Henrique
Higher cleaning effort Santiago Lima
BeloOnly Horizonte, Minas
a simple pressure cascade conceptGerais,
to the corridor can be realized
ID number: 1037317
Containment Manual
Arbeitsraum
6.2.2.2 Workspace with Common Personnel and Material Airlock
für hochaktive
Substanzen

Workspace for
highly potent
substances
Airlock
Fig. 105 Workspace with Common
Personnel and Material Airlock
Advantages To be observed
Low costs Higher space requirements than 6.2.2.1 due to the

airlock
Simple to realize Material and personnel airlock not separated,

overlap of material and personnel pathways
Multistage pressure cascade concept is possible Limited space in the airlock if there are high material
movements
Cleaning of material and personnel is possible in Higher cleaning effort for the workspace and airlock
the airlock
Low risk of propagation to the outside
Decontamination of personnel is possible in the

airlock
Arbeitsraum
6.2.2.3 Workspace with Separate Material and Personnel Airlocks
für hochaktive
Substanzen

Personnel
Airlock
Workspace for
highly potent
substances
Material
Airlock
Fig. 106 Workspace with Separate
Material and Personnel Airlocks

Advantages To Note
Multistage pressure cascade concept is Higher space requirements than 6.2.2.1 and 6.2.2.2 due
possible Mr. Bruno Henrique Santiago
to separate airlocks Lima
BeloandHorizonte,
Separation of material personnel Minas Gerais,
Higher cleaning effort for workspace and airlocks
pathways
ID number: 1037317
Low risk of propagation to the outside
Higher material movements possible
Cleaning of material and personnel is
possible in the airlock
Containment Manual
6.2.2.4 Workspace with Separate Material and Personnel Airlocks for Entrances für
Arbeitsraum
and Exits
hochaktive
Arbeitsraum
Substanzen
für hochaktive
Direction of flow
Substanzen
Personnel Personnel of personnel

Entry-Airlock Exit-Airlock Direction of flow
of material
Workspace for
highly potent
substances
Material Material
Entry-Airlock Exit-Airlock
Fig. 107 Workspace with Separate Material and Personnel Airlocks for Entrances and Exits
Advantages To Note
Low risk of propagation Expensive
Directed separate material and personnel Higher space requirements than 6.2.2.1 - 6.2.2.3
pathways
Cleaning of material and personnel is possible

in the airlocks
Multistage pressure cascade concept is possible
Fig. 107 shows a workspace concept with a separation of the entrance and exit areas as well as the
personnel and material pathways.
This arrangement ensures that in case of substance exposure, the entry airlocks are not contami-
nated if the airlocks have a higher pressure than the workspace. Subsequent cleaning can be
carried out safely as the cleaning personnel can put on their personal protective equipment (PPE)
in the entry airlock and then enter the contaminated workspace.
In the case of common airlocks for entry and exit (see sections 6.2.2.2 and 6.2.2.3) these would be
contaminated in the event of an incident.
6.2.2.5 Additional Technology Zones Separate from the Workspace

Arbeitsraum
für hochaktive
Arbeitsraum
Substanzen
für hochaktive
Technical Corridor Direction of flow
Substanzen
of personnel
Equipment 1 Equipment 2 Media
Direction of flow
Personnel Personnel
Entry-Airlock
Workspace 1
Exit-Airlock of material
for highly potent

substances
Material
Entry-Airlock Mr. Bruno Henrique Santiago Lima Material
Exit-Airlock

Equipment 3 Equipment 4
Exhaust
Filter ID number: 1037317
Technical
Technical Area
Area
Workspace 2 Fig. 108 Example Layout
with Separate Technology
Zones
Containment Manual
In the interest of better cleanability, it is recommended to only keep the most essential installations
and equipment parts in the workspace and place all other equipment and apparatus outside of the
workspace in technical areas or corridors (see Fig. 108). Further advantages are that these tech-
nical areas are freely accessible at all times for maintenance and repair work and they are not
contaminated in case of an exposure in the workspace.
Separate technical areas can be used for the installation of exhaust air filters or for media feeds.
6.2.3 Pressure Cascade Concept

The prevention of propagation of dusts through the air is an important safety measure.
Effective protection may be provided by the installation of negative pressure in the workspace by
means of a ventilation system. This is admittedly in contradiction to the GMP requirements for a
positive pressure cascade (highest pressure in workspace, lowest pressure on the outside) in order
to prevent airborne particulates from entering the workspace. In this case, the pressure cascade
concept from the perspective of protection of personnel and the environment collides with that of
the product protection perspective (GMP).
When dealing with highly potent substances, both personnel and environment protection and
product protection must be considered.
During normal operation and in the event of an incident, if it cannot be ensured that there is a lower
pressure in the primary containment than in the surrounding rooms and spaces, then the pressure
cascade concept must ensure that highly potent substances cannot escape from the surrounding
rooms and spaces.
Some possibilities are discussed in the following, along with their advantages and limitations.
6.2.3.1 Workspace with Positive Air Pressure
Workspace for + positive air pressure

highly potent
substances
R Reference point
R + Primary
Containment
Fig. 109 Positive Air Pressure Principle

There is a positive pressure in the workspace compared with the reference point.
Mr. Bruno Henrique

Advantages To Note Santiago Lima
Reduced contamination of the work- Highly potent substances could leak out of the primary contain-
space from the corridor ID number: 1037317
ment and from there into the surrounding areas
Containment Manual
6.2.3.2 Workspace with Negative Air Pressure
Workspace for R Reference point

highly potent
substances
– negative air pressure
R – Primary
Containment
Fig. 110 Negative Air Pressure Principle
There is a negative pressure in the workspace compared with the reference point.
Advantages To Note
In case of failure of the primary containment, the The workspace can be contaminated from the
highly potent substance can leak into the work- adjacent areas
space, but not from there into the surrounding
areas
6.2.3.3 Negative Pressure Corridor
A negative pressure corridor can make sense when there must be positive pressure in the work-
space, which is typically the case for aseptic production.
Entrance – Negative Pressure Corridor Exit + positive air pressure

R Reference point
Personnel Workspace Personnel
– negative air pressure
Airlock Airlock
+ +
R – + – R
+ +
Material Primary Material
Airlock Containment Airlock
– Fig. 111 Negative

Pressure Corridor
In the workspace there is positive pressure with respect to the primary containment and the nega-
tive pressure corridor. In the airlocks there is positive pressure with respect to adjacent areas
(hallways) and to the negative pressure corridor.
ID number: 1037317
Containment Manual
Advantages To Note
The positive pressure in the airlocks with respect Contaminated material and/or PPE can lead to
to the surroundings creates a barrier which contamination of adjacent areas via the airlocks,
prevents contamination from the outside entering due to the pressure drop in those areas
the corridor and workspace
Corridor serves as a pressure sink between No airlocks between corridor and workspace
airlocks and workspace means that the corridor can be contaminated if
substance escapes
Higher space requirements
The area above the workspace is not protected.

Contamination through leaks in the ceiling is
possible. The area can then only be entered
with PPE
6.2.4 Cleanroom Classifications

There are no cleanroom classes as such from the perspective of protection of personnel and the
environment. The cleanroom classification is to be defined in accordance with the quality require-
ments of the product. Accordingly, the inlet air and exhaust air systems must be equipped with the
appropriate filters.
6.2.5 Cleanrooms
Special attention must be paid to the design of the cleanrooms, as these can come into contact with
highly potent substances.
In order to achieve sufficient airtightness, cleanroom elements are installed as a rule. Classical
building frames made of stone or concrete are not optimal as these cannot be sufficiently sealed and
the surfaces are generally not suitable for intensive cleaning.
The wall and ceiling elements should have surface areas as large as possible in order to keep down
the number of joints as these are more difficult to clean and represent potential leakage points.
Grooves may be used between the walls and the floor to improve cleanability.
The ceilings are constructed from suspended, fully sealed elements with flush-mounted lamps and
ventilation outlets. Direct walking on the ceiling is not recommended as the ceiling elements may
develop leakages. It is recommended to install walkways above the ceilings with recesses for
accessing the integrated installation units.
All filters should be changeable in the direction of the workspace in order to keep contaminations in
the workspace and not propagate them into the surroundings. In contrast, lamps and other integrated
ceiling installations should be fitted and sealed flush with the room and, if possible, they should be
able to be repaired and replaced from the technical area.
Integrated installations in the workspace should be kept to the bare minimum and, if possible, located
IDAllnumber:
in a separate technical area. 1037317
wall through-holes such as pipes, cables, empty conduits, etc., must
be sealed from both sides of the wall.

All necessary accessories such as tools, samplers, buckets, shovels, etc., that have been brought into
the workspace and contaminated, must either remain in the workspace, or only be allowed to leave
once it has been ensured by cleaning and/or packaging (e. g. continuous liner system) that no
substance will be propagated.
Containment Manual
Sufficient breathable air supply connections must be installed in the workspace for the use of
PPE.
6.2.6 Personnel Airlocks

Personnel airlocks can be laid out separately from material airlocks or combined with them (see
section 6.2.2).
In principle, the same demands can be made on the design, materials, etc., of personnel airlocks
as for the workspace, since the airlocks could become contaminated. For this reason, it must be
possible to carry out a comparable, if not identical, cleaning procedure as in the workspace.
Personnel airlocks should be sufficiently dimensioned to allow enough room to be able to put on,
remove, and/or clean the personal protective equipment (PPE). Typical fittings in a personnel airlock
include:
▪▪ Washing and disinfection possibilities,
▪▪ Lockers for clothing, PPE, etc.,
▪▪ Personnel or decontamination shower,
▪▪ Eye showers (potentially also outside of the airlock),
▪▪ Breathable air supply connections as appropriate,
▪▪ Clean bench (not for work protection).
If a decontamination possibility is to be integrated into the personnel airlock, two arrangements are
possible: the linear and the parallel arrangement.
Linear Arrangement
Personnel
Airlock Decontamination Shower
Workspace for
highly potent
substances
Material
Airlock
Fig. 112 Personnel Airlock Combined with Linear
Decontamination Shower
Advantages To Note
Mr. Bruno Henrique
Decontamination airlock must be passed through
Santiago Lima
Time-consuming
when entering and leaving the workspace
ID number:No
Low risk of contamination for adjacent areas
1037317
automatic start of the decontamination airlock
on entering, manual start required
Containment Manual
Parallel arrangement
Personnel Decontamination Shower

Airlock
Workspace for
highly potent
substances
Material
Airlock
Fig. 113 Personnel Airlock Combined with Parallel
Decontamination Shower
Advantages To Note
Decontamination airlock exists, needs not neces- Decontamination airlock can be bypassed
sarily be passed through
Decontamination airlock can be used sparingly
Possible to automatically start decontamination on

every entry
The personnel airlock can be equipped with an electronic access control in order to ensure that only
trained and authorized personnel have access to hazardous areas.
6.2.7 Material Airlocks (incl. Pass-throughs, Mouseholes, Gates)

Entry to and exit from material airlocks is effected via doors (single- or double-winged), or gates in
a variety of different forms such as e. g. fast rolling gates. In all cases, the airtightness and the
chemical resistance with respect to the chemicals, cleaning and decontamination materials must be
considered and verified. From an installation perspective, the same requirements are valid for
material airlocks as for the workspace (see section 6.2.2).
In cleanroom technology, diverse special solutions are used for material airlocks. One such special
solution for example is the pass-through. In general, it serves to transfer small quantities of material
such as e. g. samples. Typical inner dimensions of such pass-throughs are 60 cm x 60 cm x 60 cm
(W x L x H ). They consist of a chamber equipped with air supply inlets and exhaust air outlets, and
a door to both the workspace and to the outer area. The doors may not both be opened at the same
time. As highly potent substances are being handled, the pass-through must be designed and
installed such that a filter change can also be made towards the interior of the pass-through or to
the workspace. Filters of the appropriate quality must be installed. Access must be provided for
carrying out leak tests.
Another special solution for material airlocks is the so-called mousehole, which is a small opening
with a directed air stream.
A closed systemBelo Horizonte,
alternative is represented byMinas Gerais,
the continuous liner airlock system, which is built into
the adjacent area from the workspace. With this system it is possible to transfer small equipment,
tools, working clothes, orIDwastenumber:
both in and out.1037317
Containment Manual
6.2.8 Decontamination Systems (Cleaning Systems)

Decontamination systems in relation to containment can include commercially available air showers,
mist showers, and liquid showers for decontaminating personnel, equipment, and rooms.
Fig. 114 – 115 Decontamination

Shower (Mist Shower)
(Left: not in operation, Right:
in operation)
Fig. 116 Air Showers
6.2.9 Ventilation
For ventilation the same requirements are valid as for the primary and secondary containment, the
workspaces, and equipment. In order to exclude cross-contaminations,it must be checked whether
the ventilation system under consideration could be connected with other systems. Circulatory
systems in which a part (in practice usually the larger part) of the air is circulated are possible in
principle, but not always allowed or reasonable. In such cases it is recommended to carry out a risk
assessment. Mr. Bruno Henrique Santiago Lima
One of the most important differences between containment and GMP requirements is the elabo-
rate filtration of the exhaust airID number:
in order to protect the1037317
environment from highly potent substances.
When considering containment requirements, all air from potentially hazardous areas (i. e. not only
during normal operation, but also in the event of disruptions) must be filtered using suitable filters
(see section 6.3).Downloaded on: 1/15/19 11:37 AM
Containment Manual
When installing filters outside of controlled areas, attention must be paid to ensure the filters there
can be changed free of contamination. It should be noted that the exhaust air channels right up to
the filter are contaminated and it must be determined how contamination of the environment can be
prevented during their cleaning.
6.2.10 Media
The media to be considered include the supply of breathable, process, and/or working air, of
nitrogen or other process gases, the vacuum supply, the supply and disposal of liquid media such
as e. g. different water qualities, wastewater and cleaning media.
The backflow of media contaminated with substance into the media supply must be avoided. This
must be ensured by appropriate measures and is a part of the risk assessment.
The collection of media contaminated with substance for disposal purposes must be ensured by
appropriate measures and is a part of the risk assessment.
6.3 De-Dusting/Filtration Technology
6.3.1 Air Filters

Air filters are used in ventilation systems to clean supply air and/or circulated air and to clean
contaminated exhaust air, for example in production facilities, laboratories, and isolation stations.
The need for clean air in industrial processes and high-tech environments continually opens up new
areas of application for air filtration.
There are a large number of different solutions for air filtration and the development already started
more than 2 000 years ago. In ancient times, desert dwellers recognized that sand dust could be
separated by means of simple cloth. In the 18th century cotton wool was used for various purposes
including e. g. in microbiological research (Pasteur) and in the processing of gold to separate
mercury vapor. During the First World War filters were developed to separate off chemical weapon
agents. Together with advances in technology and medicine and research into filtering effects, more
and more efficient filter solutions were developed. For separating out airborne particulates, aero-
sols, and sprays, today’s chemical engineering methods include the following separating systems:
▪▪ Cyclones,
▪▪ Washers,
▪▪ Electrostatic separators,
▪▪ Mechanical filter separators (fibre filters):
• Coarse dust filters,

• Fine dust Belo
filters, Horizonte, Minas Gerais,
• Airborne particulateID
filtersnumber: 1037317
such as EPA, HEPA, or ULPA filters (Abolute Filters).
▪▪ Adsorption filters e. g. activated carbon.

Containment Manual
Mechanical Air Filters

(fiber filters)
Coarse Dust Filters High-Efficiency Particulate

Cl. EN 779 G5 – G4 Air Filters (EPA/HEPA)
Dp > 10 µm Cl. EN 1822 E10 – H14
Dp < 1 µm bis 99.995 %
Fine Particulate Air Filters High-Efficiency Particulate

Cl. EN 779 F5 – F9 Air Filters (ULPA)
10 µm > Dp > 1 µm
Fig. 117 Mechanical
Cl. EN 1822 U15 – U17
Air Filters (Source
Dp < 1 µm bis 99.999995 %
HS-Luftfilterbau)
This classification takes into consideration the different filter media, the way in which the filters
separate particles and their capability to do this, and thus indirectly, the areas of application. In
addition, there are also electric filters whose mode of operation is exclusively electrostatic. With
regard to ventilation and air conditioning technology, electrostatic filters have only managed to
achieve relatively low significance in the pharmaceutical industry, mainly due to operational safety
and cost considerations. In the following, only activated charcoal filters and fibre filters are additionally
considered. The latter can be arranged as shown in Fig. 117.
Air filters in the form of mechanical fibre filters are used in most areas of technology. The most
significant areas of application are general HVAC solutions, but also in process air technology.
Typical areas of application include:
▪▪ Air conditioning systems, ventilation systems (production facilities, factories, public buildings,
offices, living quarters),
▪▪ Cleanroom technology facilities (pharmaceuticals, microelectronic, medicine, aerospace, food

industry),
▪▪ Installations to reduce emissions of toxic or radioactive substances.
A filter is a system component within a ventilation system and generally has the following tasks:
▪▪ Protection of the ventilation system from contamination and deposits,
▪▪ Ensuring a smooth distribution of airflow,
▪▪ Reduction of the particle number concentration as well as the particle mass concentration,
▪▪ Separation of odorous or gaseous pollutants (in the case of adsorption filters),
▪▪ Ensuring the hygiene requirements for room ventilation,

▪▪ Ensuring the purityBelo
class in Horizonte,
cleanrooms. Minas Gerais,
IDfor number:
For the practical use of air filters, 1037317
a given amount of air, the degree of separation with regard to
▪▪ the dust incurred (max. pure air concentration),

▪▪ the initial pressure drop and the course of the pressure drop over time, and
▪▪ the service life or the possible operating lifetime
Containment Manual
are significant factors for determining the performance and application area. These factors are
closely linked and mutually influence each other. They may change significantly depending on the
filter medium and the filter design. Additional parameters such as the effective filter surface area,
velocity of the gases, packing density, surface weight, filter thickness, etc., are required to describe
the filter specification, but they are not performance indicators.
In a ventilation system, air filters in a number of different designs, filter types, and filter classes may
be used. Depending on the area of application, the outside air, air feed, circulated air, or exhaust air
may be filtered. The air filter may be installed in the ventilation device, the duct system, or in the
ceiling or wall of the particular room under consideration. In cleanroom technology, particulate filters
may be additionally installed in laminar flow units to ensure the highest possible air purity and
low-turbulence displacement flow (v < 0.5 m/s) for critical process steps.
Knowledge about the stream of air to be cleaned serves as the basis for the selection or the design
of the air filter (mechanical fiber filters). This is determined on the one hand by the work process,
and on the other hand by the circumstances of the air conditioning and ventilation technology. Other
important influencing factors include: air temperature, relative humidity, properties of the particles
to be separated and their concentration. Next to the pressure drop, the most significant technical
factor for fiber filters is the filter class in accordance with current standards (DIN EN 779 and DIN
EN 1822).
The decisive factors in selecting which filter class to use are the application area and the particle
concentration that must be reached. The optimum selection of an air filter requires careful consid-
eration of the following criteria:
▪▪ Filter class/Quality/Cleanroom class,
▪▪ Design,
▪▪ Type of fixing,
▪▪ Design/Type of seal,
▪▪ Frame Design/Material,
▪▪ Volume flow per filter unit,
▪▪ Dimensions,
▪▪ Initial pressure drop (tolerance),
▪▪ Permissible final pressure drop,
▪▪ Maximum possible final pressure drop,

▪▪ Burst pressure (potentially),
▪▪ Test regulations/Test protocol,

▪▪ TemperatureBelo
range, Horizonte, Minas Gerais,
▪▪ Humidity range, ID number: 1037317

▪▪ Other environmental influences,
▪▪ Type of inflow.
Containment Manual
The filter performance, the pressure drop, and the capacity to collect dust, which ultimately deter-
mines the service life, are the key decisioning factors for the economic selection of an air filter. These
data are generally recorded in corresponding test certificates.
6.3.1.1 Coarse Dust Filters
Coarse dust filters nowadays are mainly used as prefilters for subsequent filtration stages. Their
area of application is intended for fibres and coarse dusts in the size range > 10 µm.
Different construction designs have established themselves for coarse dust filters, including:
▪▪ Filter pads,
▪▪ Filter cells/Cassette design,
▪▪ Wireframe filters,
▪▪ Pocket filters,
▪▪ Bags or sacks,
▪▪ Metal mesh filters.
6.3.1.2 Fine Particulate Air Filters and High-Efficiency Particulate Air Filters
Fine dust and airborne particulate filters serve to separate particulate air impurities < 10 µm. They
are, however, increasingly being used in single-stage operation to also separate coarse dusts.
The following construction designs have established themselves for fine particulate air filters:
▪▪ Filter cells,
▪▪ Pocket filters,
▪▪ Compact cassette filters,
▪▪ Combination filters,
▪▪ Filter cartridges.
The following construction designs have established themselves for High-Efficiency Particulate Air
Filters:
▪▪ Filter cassettes,
▪▪ Filter cartridges,
▪▪ Filter plates (so-called
Belo cleanroom plates),
ID number:
▪▪ FFUs (Fan Filter Units), combination 1037317
of HEPA filters with regulated fan and pre-filter where
appropriate.
Containment Manual
Fig. 118 Filter Cassette Fig. 119 Filter Cartridge
6.3.2 Handling of Air Filters

There are several basic rules to observe when handling air filters intended for use in the treatment
of room air.
Storage:
▪▪ Filters must be stored dry, preferably without contact to walls or floors.
▪▪ Filters should be kept in the original packaging until used.
▪▪ The storage areas for air filters should not be at risk for providing a bacteria-friendly medium
caused by condensing dampness.
Wet or damp filters should not be used under any circumstances and must be disposed of. Even if
the filter is dried again, it represents a health risk in the treatment of room air.
Filter Change:
▪▪ It is recommended to wear the prescribed PPE when changing a filter.
▪▪ The ventilation systems must be switched off during the filter change.
▪▪ Before installing fresh filter elements, ensure that the filter elements are free of manufacturing
defects.
▪▪ Check the mounting frame and unit seals for wear and tear.
▪▪ Check for traces of corrosion in the unit and for other signs of condensing dampness. If wetness/
corrosion is present, then the cause must be remedied.

▪▪ Used filter elements may be contaminated with hazardous materials and/or harmful concentra-
tions of microorganisms and represent a health risk. Therefore they must be professionally
packed after removal.
ID number: 1037317
▪▪ Used filter elements must be immediately disposed of. Do not store used filter elements in areas
where they may be mixed with fresh filters or lead to health risks (e. g. do not store near to food).
▪▪ Used filter elements that may still seem usable must not be reused for other areas of application!
Containment Manual
Use of High-Efficiency Particulate Air Filters and Compact Filters:
▪▪ Take care when unpacking airborne particulate filters not to damage the seals. Foam seals can
be easily destroyed by shear force.
▪▪ Avoid touching the filter surface. This is very sensitive and can be damaged by inadvertent
contact.
▪▪ Even the smallest damages to the filter surface can make airborne particulate filters unusable.
Do not try to fix any damages if you have no measurement device available to subsequently test
the separation efficiency.
▪▪ High-Efficiency Particulate Air Filters are to some extent rather heavy, unwieldy and bulky
(610 mm x 610 mm x 292 mm) and can weigh up to 20 kg in the non-loaded state. Filter changes
and storage movements should best be carried out by two people.
▪▪ Always check for correct fit of the filter in the mount, as tilts can lead to bypasses.
▪▪ In case of filter applications in safety-relevant facilities (ceiling outlet in operation rooms, process
air in pharmaceutics production, etc.) it is recommended to use a fit test device to ensure a
bypass-free installation.
Handling of Pocket Filters:
▪▪ Take care to ensure that the filter media are not torn by sharp edges or tools during installation.
Damaged filters cannot be repaired by the user and must be disposed of.
▪▪ Pocket filters must be aligned standing vertically. Filter pockets that are jammed must be freed or
the filter surface area cannot be used to its full extent.
▪▪ Take care during installation to ensure that all filter pockets are aligned vertically. Horizontally
“lying” filter pockets do not allow for an optimum through-flow and could lead to contact with
condensing dampness.
▪▪ Always wear the prescribed PPE when handling pocket filters made of glass fibres. The fibre
dusts can irritate the eyes and respiratory tract.
6.3.3 Exposure Measurements at Filter Units

In order to achieve compliance with the targeted containment level, it is recommended to carry out
exposure measurements at both the production units and at the connected filter units. Filter units
must be maintained and repaired at regular intervals, whereby filter changes and emptying of
discharge containers represent an elevated risk to the containment. This risk must be eliminated
by the use of suitable technology. Specifically, this entails the use of Safe-Change technology,
continuous liner systems, and also glove boxes, RABS or isolators for certain areas of the filter unit.
Experience gained from exposure measurements carried out on filter units show the following
results. Mr. Bruno Henrique Santiago Lima
ID number: 1037317
Containment Manual
Filter safe change and

wetted filter cell
< 1 µg/m3
Filter safe change dry
1 – 10 µg/m3
10 – 100 µg/m3
Filter change without

protection bag
100 – 1 000 µg/m3
> 1 000 µg/m3 Fig. 120 Results of Exposure

Measurements on Filter Units
The filter changes measured here represent a time range of about 20 – 30 min and must be inter-
preted in relation to e. g. the number of chambers in the filter unit and to the time period under
consideration (eight working hours or short-term exposure).
6.3.4 Local Aspiration and Central Aspiration

A differentiation is made in the classification of filter units in production processes between central
aspiration and local aspiration. In the case of local aspiration, a specific filter unit is assigned to a
particular production unit and usually installed in close proximity. In contrast, central aspiration is
used when several aspiration points must be served by a single filter unit. Such filter units are high-
volume and usually located in technical areas and connected via a pipeline network. Both variants
have advantages and disadvantages in relation to the containment level to be maintained. In indi-
vidual cases and where subsequent modifications or retrofitting of production facilities have become
necessary, a combination of both local and central aspiration may be encountered.
Production
unit
Fig. 121 Local Aspiration
Local aspirations (Fig. 121) prevent product propagation and cross-contamination. A simple decon-
tamination of the filter unit can be achieved. Maintenance work such as filter changes and emptying
discharge can be carried out in the production room. Short pipelines can be implemented, which
ensures better cleanability.

Production
unit 1

Production
unit 2

Production
unit 3
ID number:
Fig.1037317
122 Central Aspiration
Containment Manual
Central aspirations (Fig. 122) have lower cost of investment in the case of a high number of produc-
tion machines. The place of installation does not necessarily have to be in the vicinity of the
production. It must be noted that cross-contamination may not fully be ruled out. The cleaning of the
connected pipelines may be difficult or impossible.
Production
unit 1
Production
unit 2
Production
unit 3
Fig. 123 Mixed Concept
Mixed concepts (Fig. 123) are possible if e. g. certain production lines have different containment
requirements. The combination of the advantages and disadvantages of the local and central solu-
tions must be considered in each case.
6.3.5 Safe Change Filter Systems

When changing contaminated filters, the operator must be protected from the potent product. For
this there are a number of different systems available. The following most common systems are
given as an example:
▪▪ Push-Push Filter Systems,
▪▪ Bag-In/Bag-Out Change Method (BIBO).
6.3.5.1 Push-Push Filter Systems
The contaminated filter cartridge is replaced by a new one by being pushed into the isolator with the
help of the new cartridge. The new filter cartridge takes the place and the role of the old cartridge.
The old filter cartridge can be disposed of in the isolator in a contamination-free manner.
This Document is licensed to Fig. 124 Schematic Depiction of a Push-

Push Filter Change on a Supply Air Filter
Mr.
6.3.5.2 Bag-In/Bag-Out Bruno
Change Henrique
Method (BIBO) Santiago Lima
Using the safe change method, it is possible to carry out a largely contamination-free filter change.
ID onnumber:
The safe change method is used 1037317
filter units both when changing cassette filters and when
discharging collected dusts.

For simplicity, the following explanations deal with the exchange of cassette filters. In the case of
the protective bag change method, an change frame is fitted on the door frame of the filter chambers.
Containment Manual
The change frame consists of a perimeter aluminium profile with two perimeter grooves. The protec-
tive bag is pulled over the change frame and fastened with an O-ring. The O-ring lies in the perimeter
groove and thus hermetically seals the protective bag against the change frame (Fig. 125).
Change Frame
Rear Groove
Front Groove
Protective
Bag
O-Ring Fig. 125 Change Frame
In order to change the filter, the following work sequence must be adhered to. Otherwise it is not
possible to ensure the work is contamination-free.
1. Removing the contaminated filter:
Plastic Bag
▪▪ Switch off filter unit and remove
Loaded
Filter corresponding maintenance
Element door
▪▪ Roll out protective bag
▪▪ Loosen filter cell and carefully

O-Ring
pull into protective bag
Fig. 126 Removing Contaminated Filter (Fig. 126)
Safety Note:
In order to avoid damage to the protective bag, filters should always be changed by two people.
As the contaminated filter cell stores a considerable amount of dust, it can weigh up to 60 kg. It
is therefore advisable to ready a suitable place to put the filter cell in front of the filter chamber
before removing the filter cell.
2. Packing the Contaminated Filter:
Remaining Piece of Bag

Loaded
Filter
▪▪ Press the protective bag
together between the filter cell
Element and the filter chamber
▪▪ Tie and seal the protective bag
Belo Horizonte, Minas Gerais, in two places as close together
as possible
IDSystem
Manual Closure number: 1037317
▪▪ Cut the protective bag between
Fig. 127 Packing the Contaminated Filter the two ties (Fig. 127). Push the
Downloaded on: 1/15/19 11:37 AM filter cell into a suitable trans-
port packaging
Containment Manual
Note:
Tools with high containment level technology may be used for separating the protective bag e. g.
crimp sealing systems.
3. Preparing the New Filter Cells Before Insertion:
Second O-Ring
▪▪ Push new filter cell into a new
Remaining Piece of Bag suitable protective bag
▪▪ Pull O-ring over the open end of

the protective bag
▪▪ Put protective bag over the

New Plastic Bag change frame
with New Filter Element First O-Ring
▪▪ Press O-ring into the second
Fig. 128 Preparation of a New Filter groove (rear)
(Fig. 128)
Important:
The correct selection of the protective bag and the perimeter O-ring is decisive for a contamina-
tion-free filter change. The protective bag should be made of transparent polyethylene. Bags with
a thickness of 0.14 mm and a length of at least 2 m have proven themselves especially. The
perimeter of the bag should be at least 2-5 cm larger than the perimeter of the change frame.
The O-ring should have a diameter of 10 mm. The circumference of the O-ring must be signifi-
cantly smaller than that of the collar so that the O-ring fits tightly into the groove.
4. Removing the remaining piece of the bag and inserting the new filter
In order to insert the new filter into the housing, the rest of the remaining piece of the bag and
the O-ring of the contaminated filter must be removed. These remain in the new protective bag
and will be disposed of at the next filter change.
New Plastic Bag

Remaining Piece of Bag ▪▪ Grab the remaining piece of the
bag through the new protective
bag and pull it off
▪▪ Place the O-ring and the

This Document is licensed to remaining piece of the bag in
front of the new filter
New Filter Element
▪▪ Push the filter cell into the
Fig. 129
Mr. Bruno Henrique Santiago
Inserting a New Filter
Lima
housing to the limit (Fig. 129)
Belo Horizonte, Minas ▪Gerais,
▪ Tighten the filter cassette
ID number: 1037317
Containment Manual
5. Rolling in the Protective Bag
New Plastic Bag

▪▪ Fold the protective bag side-
ways to approx. 60 cm
▪▪ Roll in the protective bag and

press it in front of the filter
(Fig. 130)
New Filter Element
Fig. 130 Rolling in the New Protective Bag
Note:
In order to prevent an unintentional roll back of the bag, it can be fastened with an adhesive strip.
The bag must be pushed into the filter housing so that it does not extend out of the change
frame. This would otherwise make it difficult to close the maintenance door.
6. Changing the O-Ring in the Front Perimeter Groove:
Before the filter cell can be changed again, the O-ring located in the rear perimeter groove must
be removed and replaced by a new one in the front groove.
▪▪ Pull another O-ring over the

change frame and place it in the
front groove (Fig. 131)
▪▪ Lift the O-ring from the rear

groove and pull it over the
change frame
▪▪ Fold the collar of the protective

Fig. 131 Fig. 132 bag so that the rear groove is
free for the next change
(Fig. 132)
7. Closing the Maintenance Door:

• Fully roll up the protective bag.
• Replace the maintenance door.

• Gently tighten the screws until the door is evenly sealed.
ID number: 1037317
Containment Manual
Note:
Before finally sealing the maintenance door, it should be checked that the protective bag is fully
behind the door. If the protective bag is jammed in the sealing area of the door, this can lead to
damages and leakages.
Fig. 133 – 135 Inserting the Filter

ID number: 1037317
Containment Manual

ID number: 1037317
7 Occupational Hygiene/
Industrial Hygiene Validation

ID number: 1037317
ID number: 1037317
ISPE D/A/CH COP CON 7 Occupational Hygiene/Industrial Hygiene Validation
Containment Manual
7 Occupational Hygiene/Industrial

Hygiene Validation
Occupational hygiene validation (not GMP validation) of an equipment or part of an equipment,
refers to the quantitative verification of the tightness of these installations with respect to harmful
substances.
As the majority of pharmaceutical substances are solids and the exposure potential in handling
solids is highest, the focus of this manual is placed on the validation of the tightness with respect to
solids. The manual does not address liquids, vapors, and gases.
7.1 Basic Principles

The occupational hygiene validation is carried out by measuring the concentration of the chemical/
pharmaceutical substance or substitute material in the air using validated measurement techniques.
“Validated measurement techniques” means that both the sampling method as well as the analysis
of the sample must be validated. In addition, surface measurements are carried out.
7.2 Strategy
The strategy of the occupational hygiene validation is derived from the information on the technical
devices installed and from the process flow. For which process steps should the exposures be
evaluated? How often are these process steps carried out and how long do they take?
The measurement conditions should be chosen to be as representative as possible for the process
flows to be evaluated. The exposure measurements should be carried out on a sufficient number of
days and during all significant process steps.
The exact measurement strategy can be worked out based on this information and the specific
respective question catalogue.
7.3 Validated Sampling Method

A human being does not breathe in all fractions of a particle mixture to the same extent, nor are
these taken up evenly in the respiratory tract.

Particles with a diameter greater than 10 µm are hardly taken up at all in the lower respiratory tract
(pulmonary alveoli/air sacs). Particles larger than 50 µm only in the upper respiratory tract.
Only about half of these large particles (>50 µm) are even breathed in, i. e. half of these large
particles remain outside when breathing. Nevertheless, these large particles have a relatively large
mass and are thus, from a toxicological standpoint, much more relevant than smaller particles
whose mass decreases exponentially with diameter (a particle of 1 µm diameter has a mass 1000x
ID number: 1037317
smaller than a particle with 10 µm).
7 Occupational Hygiene/Industrial Hygiene Validation ISPE D/A/CH COP CON
Containment Manual
Particle Diameter (µm) Volume (cm3) Surface Area (cm2)
0,1 5,23 ∙ 10 –16 3,14 ∙ 10 –10
1 5,23 ∙ 10 –13 3,14 ∙ 10 –8
10 5,23 ∙ 10 –10 3,14 ∙ 10 –6
100 5,23 ∙ 10 –7 3,14 ∙ 10 –4
1000 5,23 ∙ 10 –4 3,14 ∙ 10 –2
Tab. 2 Particle Parameters: Spherical Diameter, Volume, and Surface Area of Particles
With regard to industrial hygiene, it is assumed the particles of most substances entering the
respiratory tract from the nose down to the pulmonary alveoli are also taken up by the body. The
assimilation can take place directly at the place of entry (mucous membranes of the respiratory
tract), or the particles may be transported via mucous or by the activity of the ciliated epithelium in
the upper respiratory tract to the throat and swallowed. The assimilation of particles originally
breathed in then takes place via the mucous membrane in the gastrointestinal tract.
Fig. 136 Site of Particle Deposition

ID number: 1037317
Fig. 137 Inhalable Particle
Fraction
Containment Manual
The proportion of particles present in the air that is breathed in, independently of which point in the
respiratory tract the particles are then assimilated, is called the “inhalable fraction”, also known
previously as “total [inhalable] fraction”. This fraction is more precisely defined in the ISO Norm
7708 (EN 481).
An ideal measuring head (also known as measuring cassette or sampling head) would pick up
precisely this inhalable particle fraction. The IOM (Institute of Occupational Medicine) measuring
head comes very close to this ideal.
Investigations have shown that depending on the product, a relevant proportion of the dust collected
is not deposited on the filter, but rather on the two-part filter mount (“inserts”, see arrows). For this
reason, the filter desorption should always take place “in situ”, i. e. the filter mount should be placed
in the desorption solution still mounted together with the filter. This additionally avoids manipulations
on the filter itself, which could lead to a loss of collected dust. The filter inserts are commercially
obtainable in plastic or metal. If plastic inserts are used, their resistance against the solvent used
must be validated.
Fig. 138 IOM Measurement Head
Additional measurement heads which collect dust relatively well in accordance with ISO 7708 are
the English seven-hole sampler and the conical sampler commonly used in Germany. A specific
flow rate is given for every measurement head.
Fig. 139 – 141 Other Common Measurement Heads

In the USA a plastic cassette is widely used which is available in 25 mm and 37 mm versions. This
cassette has a number of advantages (single-use, in situ desorption generally possible). If a meas-
urement is to be made according to ISO 7708 then this measurement head should not be used as
it delivers measurement results that are too low.
ID number: 1037317
7.4 Validated Sample Analysis
In rare cases a gravimetric measurement may be considered. For this the measurement filter is
weighed before usage, placed in the measurement head, and a known amount of air is sucked
through the filter. The filter is then weighed again and the total inhalable fraction is calculated in
µg/m3 from the weight difference and the amount of air filtered. This method is unspecific, however,
Containment Manual
and only weight differences >10 µg are usable i. e. the gravitational measurement method is not
sensitive enough in many cases. In most cases a substance specific analytical method is used for
the exposure measurements (HPLC, LC-MS, LC-MS/MS, etc.).
In order to validate such measurement methods, in addition to the usual parameters also valid for
QC laboratory measurement methods (selectivity, specificity, linearity, precision, sufficient sensi-
tivity), the following validation parameters are also used
▪▪ Recovery rates for the elution of the filter (choice of the best filter material),
▪▪ Stability of the collected material when air is continually pass through the filter,
▪▪ Stability of the collected material on the filter (different storage periods and different storage
temperatures).
The validation of the method is a necessary quality assurance measure. The general principle is
that the scope and effort of the validation should stand in a reasonable relationship to the require-
ments placed on the method.
7.4.1 Selectivity and Specificity

Selectivity refers to the ability of a method to collect and clearly identify different components to be
determined in parallel and without interference to one another. In contrast, specificity is the ability
of a method to collect and clearly identify a substance or a substance class without falsification
caused by other components in the sample.
7.4.2 Linearity
A method is linear within a specified concentration range when the measurement signal is directly
proportional to the concentration of the substance being analyzed in the sample.
7.4.3 Limit of Detection and Limit of Quantification

The sensitivity of a method is reflected by the limit of detection and limit of quantification.
The limit of detection (LOD) indicates the lowest possible detection amount.
The limit of quantification (LOQ) indicates the lowest quantifiable amount i. e. the amount that may
only just be correctly quantified with a specified correctness and precision.
As a rule, the requirements on the sensitivity of the measurement method are determined based on
the following specifications: For an operating duration of at least 30 min, it should be possible to
determine a substance amount of 10 % of the OEL. This sample is generally taken at a rate of
2 l/min and the filter eluated with 2 ml of solvent.

For a substance with an OEL of 1 µg/m3 this would lead to a required limit of quantification of
3  ng/ml. Belo Horizonte, Minas Gerais,
ID number: 1037317
7.4.4 Precision and Accuracy
Precision refers to the measure of agreement of independent analysis results amongst each other,
or to put it another way, a measure of the statistical scattering. Accuracy refers to the information
about the deviation of the average value from the correct value. This deviation is caused by system-
atic errors.
Containment Manual
7.4.5 Recovery Rate

The recovery rate is the relationship between the average value of the analyte in the sample meas-
ured under repeatable conditions and the correct value. The recovery rate is used to prove the
accuracy of the entire method.
x
Formula for the Recovery Rate: W = ×100 %,
m
with: W Recovery rate in percent,
x Average measured value,
Correct value.
µ
The ideal value for W is 100 %. The entire method can be evaluated by the recovery rate, since if
µ is found, then the selectivity, the accuracy, and the robustness is proven for the given conditions.
The filter material must have been tested for its suitability by means of recovery rate tests. The
substance to be determined must be able to be eluated from the filter and be stable on the filter for
the time period from the sampling until it is processed.
Ideally, the recovery rate should be 100 % (typical acceptance limits: ≥ 80 % and ≤ 110 %).
In order to determine the recovery rate and the degree of efficiency of desorption, the filters or
swabs, and for checking purposes the eluent (mobile phase) are analytically examined with solu-
tions of specific concentrations. Generally, the eluent is spiked with substance in three concentra-
tions: one close to the detection limit of the method, one in the region of the OEL, and one at a
multiple of the OEL.
In order to test the stability, a portion of the samples with lower concentration are stored for 15 or
30 days at –20 °C and then analyzed as well.
For all measurements blank filters (non-exposed filters) and so-called spiked filters are handed in to
the laboratory. Spiked filters have had a known amount of substance added to them and generally,
here as well, three different concentrations are added
7.5 Procedure
A relatively large amount of effort goes into a measurement campaign. It cannot, therefore, be
repeated any number of times and must be carefully prepared. The following questions must be
answered:
▪▪ Which substance should be measured?

A containment which is already in operation can best be validated by measurements on a
substance which is produced there. If it is a multipurpose equipment, then generally the “worst
case”is selected (often a combination of criteria such as low threshold value, large volumes/
ID number: 1037317
frequent campaigns, low or even no dilution with excipients, high tendency to form dusts).
New equipment is often measured with a surrogate material i. e. the process is simulated using
substitute material. Popular surrogate materials include lactose, naproxen, and paracetamol.
When preparing the sampling method, it is important to refer to the method validation document
to see what the correct filter material is for the substance to be measured.
Containment Manual
▪▪ How often should a measurement be made?
At a minimum, each process step should be measured in three separate independent passes. If
these values scatter strongly, then further measurements are required.
▪▪ What should be measured?
For an estimation of the actual exposure of the worker, a personal measurement is the most
important. This is carried out by attaching a measurement cassette in the breathing area of the
worker and measures what the worker breathes in.
For every other (stationary) measurement point, it must be clarified what exactly should be
measured i. e. a measurement strategy should exist. Should the amount of dust be measured
• Directly at the (assumed) source (worst case)?
• At a larger distance from the source in the workspace itself (propagation of the contamination)?
• In the airlock or in the “clean corridor” (validation of the secondary containment)?
The results of stationary measurements cannot be directly compared with the OEL.
In accordance with CEN EN 689, sampling should take place as far as possible at breathing
height and in direct proximity to the workers. This is admittedly only reasonable when stationary
measurements serve as a replacement for personal measurements. For primary containment
measurements it is imperative that personal measurements are carried out and not stationary
substitute measurements. Stationary measurements may make sense as a substitute for
personnel measurements if e. g. it is intended to measure in the worst case what amount of
substance could be breathed in by an unprotected person located in a “clean” corridor outside of
the production room.
If there should be any doubt about the precise positioning of measurement heads, then the place
of higher risk should be selected. This must be taken into consideration when interpreting the
results, however.
The ISPE Good Practice Guide “Assessing the Particulate Containment Performance of Pharma-
ceutical Equipment (SMEPAC)” provides details on how to select stationary measuring points.
The objective is to have a better comparison of containment measurements.
▪▪ When should measurements be carried out?
As a rule, containment measurements are carried out during the site acceptance test (SAT). The
SAT refers to the validation of the correct functioning of the equipment in accordance with the
specifications after it has been installed at the customer. These measurements can either be
carried out using a surrogate substance or during one of the first commercial uses of the contain-
ment i. e. the “real” product is measured. As no surrogate behaves exactly like the real product,
subsequent measurements must be carried out with the real product even if the SAT is performed
successfully with the surrogate substance. Measurements with surrogate material are still useful,
since they can provide important insights for subsequent measurements with the real product.
Experience shows that containment measurements during the SAT often give poor results,
because the operator ID
is stillnumber: 1037317
inexperienced with the equipment and situations are measured that
do not occur later on. SATs should therefore only be carried out once at least a minimal routine
has been gained in working with equipment. Until the SAT has been successfully validated, for
safety reasons personnel must wear personal protective equipment. .
Containment Manual
7.6 Evaluation of the Occupational Hygiene Measurement Results

In evaluating the personal measurement data, the measurement results are compared with the
OEL.
As a rule, such a comparison is not appropriate in the case of stationary measurements. Rather, the
results must be considered together with the question catalogue used for selecting the stationary
measuring points.
The ISPE Good Practice Guide “Assessing the Particulate Containment Performance of Pharma-
ceutical Equipment” describes a pragmatic way of evaluating the results. Before the measurement
takes place, the user must make a statement as to what containment is expected (User Require-
ment Specification). The measurement results are thus directly compared with these specifications.
The results of the air measurements are given as an average value over the effective duration of
the process step. There is no conversion of the results to an 8-hour average value. Many compa-
nies set a target during the planning of the equipment to stay below the threshold value for every
single process step measured. The rationale is that within a shift in individual worker often has to
carry out numerous process steps each with different possible exposures, and these process steps
are not always plannable. Compliance with the OEL in every process step, taking into consideration
the evaluation of the exposure to substance mixtures, makes it possible to assign the workers in a
shift with any task, without the total shift average of the OEL being exceeded.
Different regulations and norms address the topic of exposure determination. In the following, only
those relevant in the German-speaking area are discussed.
The German TRGS 402 describes the survey of the result as follows:
▪▪ If the exposure result determined is higher than the average value, then the threshold has not
been adhered to and measures must be taken immediately to reduce the exposure and then new
exposure measurements must be carried out.
▪▪ If the exposure result determined is smaller than or equal to the threshold value and if the require-
ments related to short-term exposure peaks are fulfilled, then the threshold is adhered to.
If, however, due to temporal and spatial fluctuations in the inhalative exposure, the result “protective
measures sufficient” cannot be verified, then it must be explained why the fulfilment of the prereq-
uisites for the result “protective measures sufficient” is expected in future.
Possible reasons for this could be:
▪▪ The investigations were carried out for the most unfavourable conditions (worst case), so that in
normal operation lower loads are to be expected.

▪▪ The relevant boundary conditions are stable in the long term. It is ensured that the relevant
boundary conditions will change only insignificantly, so that relatively low fluctuations in exposure
are to be expected. This can be validated e. g. by the results of earlier control measurements.

▪▪ Due to continuous monitoring, suitable protective measures will be triggered if a predetermined
concentration is exceeded.
▪▪ Due to continuous or regularID number:
control 1037317
the effectiveness of the protective measures is ensured that
suitable protective measures will be triggered based on predefined criteria.

▪▪ Experience from similar workplaces have shown that in the long term the fulfilment of the pre-req-
uisites for the result “protective measures sufficient” can be expected.
Containment Manual
For the evaluation of exposure described in the literature, a sufficient number of measurement
values is required. This is the only way to make a meaningful (statistical) evaluation.
In practice, however, it is shown that only a few measurements can be carried out and a larger
number of measurements does not necessarily lead to a significant improvement in the statement
about compliance with a threshold value.
The following evaluation is often made based on the TRGS 402 and the CEN EN 689 and in
accordance with the following statistically reasoned criteria:
▪▪ Measurement value ≤ 10 % of the threshold value:
Threshold value definitely complied with → No measures necessary.
▪▪ Several measurement values (at least 3) ≤ 25 % of the threshold value:
Threshold value definitely complied with → No measures necessary.
▪▪ Several measurement values between 25 % – 100 % of the threshold value:
Threshold value possibly not always adhered to → Verify the situation to what extent the
threshold value can be adhered to; Check and implement possible measures of improvement;
Possibly additional measures required to verify
▪▪ Several measurement values> 100 %:
Threshold value not adhered to → Implement immediate measures
It is important to not consider evaluation as a mere comparison of threshold values and measure-
ment values. The measurement values must always be weighted in relation to the observations
made and the given situation. The available results must have been obtained from typical process
steps in order that they can be regarded as representative. The exposure can never be precisely
determined. For one thing, inaccuracies arise from measurement techniques e. g. in sampling and
analysis. In the case of less automated processes there may be large fluctuations from day to day
or between different workers.
The quality of the measurements and the measurement strategy have a great influence on the
reliability of the possible statement. It must be taken into consideration that the measurements must
be announced in the majority of cases, so that the desired handlings can be recorded. It is standard
practice that the occupational hygienist is present during the measurements.

ID number: 1037317
8 Cleaning/Waste Treatment

ID number: 1037317
ID number: 1037317
ISPE D/A/CH COP CON 8 Cleaning/Waste Treatment
Containment Manual
8 Cleaning/Waste Treatment
8.1 Process Systems

Most of the contaminated residues resulting from the process systems mentioned in this manual are
incurred in the form of production waste, packaging waste, filter waste, and cleaning waste. These
residues/wastes come in solid and/or liquid form.
The following table provides an overview of the waste types that can be expected, but it may not be
exhaustive:
Containment System Production Packaging Filter Waste Cleaning

Waste Waste Waste
Isolators yes yes yes yes
Granulators yes no yes yes
Dryers yes no yes yes
Grinding Units yes no yes yes
Tablet Press yes no yes yes
Coaters yes no yes yes
Capsule Fillers yes no yes yes
Laminar Flow Systems yes yes yes yes
RABS yes yes yes yes
RTP Systems yes yes no yes
Split Butterfly Valve Systems yes no no yes
Split Cone Systems yes no no yes
High Containment Liner yes yes no yes

Connector Systems
Flexible Containment Transfer yes yes no no

Systems
Powder Transport Systems yes no yes yes
Cleanrooms
Safety Cabinets
yes
yes
yes
yes
yes
yes
yes
yes
Tab. 3 Waste Types

ID number: 1037317
8.1.1 Treatment of Production Wastes
Following a production process, lesser or greater amounts of residual substance may still be
present within the systems. These are often found as adhesions and/or dust deposits on the inner
surfaces, but also on equipment and accessories such as e. g. weighing scales and scoops required
for the process.
8 Cleaning/Waste Treatment ISPE D/A/CH COP CON
Containment Manual
A contamination-free outwards transfer of all residual amounts should be made possible via airlocks
(see section 8.3 “Airlocks”). Adhesions and dust deposits on surfaces can for example, if technically
possible, be pre-cleaned with an integrated vacuum cleaner in order to reduce the amount of
residual substance in the rinsing liquid. All highly potent production wastes removed via airlocks
must subsequently be subjected to a controlled waste disposal procedure.
The final cleaning or decontamination is ultimately carried out with a cleaning medium such as e. g.
water (see section 8.4 “Cleaning Media”).
8.1.2 Treatment of Packaging Wastes

The introduction of a highly potent substance e. g. into a weighing isolator, is normally carried out in
the original packaging or partial packaging via double chamber airlocks or RTPs. The packaging
components become unavoidably contaminated with the substance when opening and processing
the substance (see section 8.3 “Airlocks”) and must subsequently be removed in a contamina-
tion-free manner via airlocks. The removed packaging components must subsequently be subjected
to a controlled waste disposal procedure.
8.1.3 Treatment of Filter Wastes

Many containment systems require both supply and exhaust air ventilation for operation. The
exhaust air passages should preferably be equipped with suitable filters in order to prevent the
contamination of the surroundings. Normally the exhaust air filters are removed from or exchanged
in the system using a “safe change” (“bag-in/bag-out” or “push-push”) method (see section 6.3
“De-Dusting/Filter Technology”). Whereas in the bag-in/bag-out method the packed filter can be
directly fed into the controlled waste disposal procedure, in the push-push method, the cartridge
filters are pushed into the containment system and must be removed from it in a contamination-free
manner via airlocks (see section 8.3 “Airlocks”). They must then be fed into a controlled waste
disposal procedure.
8.1.4 Treatment of Cleaning Wastes

Cleaning wastes often present themselves in liquid form as solvents, dilute bases and acids,
tensides and water, and mixtures of these components in various concentrations. This type of
“liquid” waste is caused by the decontamination or washing/rinsing of the containment systems and
must be drained back out of them. The drainage should preferably be carried out in closed pipeline
systems with connected tanks. Although the aqueous mixture of highly potent substances and
cleaning agents present a considerably lower risk to people, dried cleaning wastes e. g. on the floor,
do present a risk once again (see section 8.4 “Cleaning Media”).
Accessories such as brushes, sponges, cleaning cloths, etc., must be removed from the contain-
ment system in a contamination-free manner via airlocks (see section 8.3 “Airlocks”). After use, they
must be fed into a controlled waste disposal procedure or may be reused after cleaning.

ID number: 1037317
Containment Manual
8.2 Rooms
Contaminated wastes may ensue in various forms in rooms in which containment systems are
installed (see Table 3 in section 8.1). Particular attention must be paid to the exhaust air filters in
these rooms as these may be in operation for longer periods and be highly contaminated. They may
thus present a hazard during dismantling or when being changed.
The filters should ideally be exchangeable using a safe change method (see section 6.3 “De-Dusting/
Filter Technology”). Alternatively, due to the low change intervals, the use of PPE (single-use
protective suit with corresponding breathing protection) may be considered. If a filter change is
carried out using PPE, an appropriate decontamination possibility must be available and the
resulting wastes must be fed into a controlled waste disposal procedure.
All surfaces in the rooms and on the installed containment systems should be wiped with aqueous
cleaning agents at regular intervals depending on the production frequency in order to prevent a
buildup in concentration of residual adhesions on the surfaces. If this approach is ensured, then the
resulting liquid cleaning wastes present a lower, tolerable hazard and can be fed into the normal
wastewater channels. Accessories such as brushes, sponges, cleaning cloths, etc., must be
removed from the containment system in a contamination-free manner (see section 8.3 “Airlocks”).
After use, they must be fed into a controlled waste disposal procedure or they may be reused after
cleaning.
An exception to this is the “disaster case”. If large amounts of product with highly potent substances
should escape from a containment system, then the exhaust filters must be exchanged and
disposed of as described in the section above. All liquid cleaning wastes must be fed into a special
disposal procedure.
8.3 Airlocks
8.3.1 Material Airlocks in Containment Systems

Material airlocks are used for introducing and removing raw substances, materials, processing
equipment, packaging materials, and cleaning equipment.
As described in section 8.1, waste may also occur in the material airlocks in the form of residual
product, dusts, and packaging materials. In the case of aqueous cleaning, liquid cleaning wastes
may also result. All ensuing wastes must be treated as described in section 8.1.4.
8.3.2 Waste Airlocks in Containment Systems

Since it is disadvantageous to transfer wastes back out via the material inlet airlocks, containment
systems may be equipped with a separate waste airlock in order to separately remove wastes from
the system in a contamination-free manner.

In practice, rapid transfer ports coupled with continuous liners (film tube) have proven themselves.
In this case, the contaminated wastes can be furnished with a protective overpack and fed into a
controlled waste disposal procedure.
ID number: 1037317
Waste airlocks can be contaminated with highly potent substances during operation and when
transferring material out. Appropriately, they must be cleaned with aqueous cleaning agents and the
resulting cleaning wastes should be treated as described in section 8.4.2.
Containment Manual
8.3.3 Personnel, Material, and Waste Airlocks in Production Rooms and Sections
Production rooms and production sections in which highly potent substances are processed in
containment systems, must be equipped with airlocks. There is a large variety of designs available
(see section 6.2).
Once a correctly functioning waste disposal procedure within the containment systems and the
adjacent production rooms has been established, no higher exposure is to be expected in the
material and waste airlocks (exception: in case of an incident). Accordingly, no separate waste is
produced.
Personnel airlocks should be equipped with a decontamination possibility for worn PPE. In practice,
the decontamination of the PPE is carried out by wetting with water or water/tenside mixtures. The
PPE is then taken off and cleaned or disposed of.
Any wastewater resulting from this should be treated as described in section 8.4.2. PPE waste
should be fed into a controlled waste disposal procedure.
8.4 Cleaning Media
8.4.1 Water as a Cleaning Medium
8.4.1.1 Background
Water is often used for cleaning in a variety of different qualities; this holds for pre-cleaning, main
cleaning, and final cleaning.
8.4.1.2 Types of Water Used
The following types of water are used for cleaning at various temperatures:
▪▪ Potable water,
▪▪ De-ionized water (demineralized water),
▪▪ Purified water,
▪▪ Water for injection.

8.4.1.3 Detergents and Cleaning Agents
Many pharmaceutical APIs and their mixtures are poorly soluble in water. For this reason, depending
on the product/substance, various detergents must be added in different concentrations. Diverse
solvents may also be used.
ID number: 1037317
8.4.1.4 Washing Procedures
In order to free a containment system as far as possible from API residues without opening it, thus
protecting personnel and equipment from contamination, closed system cleaning processes are
used. During the cleaning process, contaminated surfaces are wetted or cleaned with the cleaning
media by means of spray nozzles. The ensuing wastewater must be collected and disposed of.
Containment Manual
Generally, a differentiation is made between the following washing procedures:
▪▪ WIP = Washing in Place:
Diverse cleaning processes serve to remove and bind product contaminations. Once sufficient
decontamination has been achieved, the system may be opened and a final cleaning carried out.
The timing of the opening is dependent on the product and must be set in advance by an evalu-
ation.
▪▪ CIP = Cleaning in Place:
Largely automated cleaning process without manual intervention and without opening the system.
The cleaning process is set in advance such that the cleaning result may be fully validated and
reproducible. Subsequent manual cleaning is not necessary with this process.
8.4.1.5 Various Cleaning Cycles
For economic reasons it is recommended to split the cleaning into various cycles.
A reasonable division may be as follows:
Rinse Cycle Water Type Wastewater Type
First rinse Potable water Hazardous wastewater (collected sepa-

rately)
Second and subsequent rinses Potable water Hazardous wastewater or plant waste-
water
Last rinse Purified water Plant wastewater
Tab. 4 Example of Rinse Cycles
The timing of the switch between hazardous wastewater and plant wastewater is dependent on the
product and must be specified in advance by an evaluation.
8.4.2 Disposal of Wastewater

As described in sections 8.4.1.4 and 8.4.1.5, parts, or even all, of the wastewater must be collected
and treated as hazardous wastewater.

For this, wastewater tanks must be made available and e. g. mobile tanks (see Fig. 142) may be
used. Once full, these can be removed and exchanged by disposal specialists (in-house/external).
Collection in a permanently installed tank (see Fig. 143) with subsequent emptying for final disposal
is also possible.
ID number: 1037317
Containment Manual
Fig. 142 Mobile Hazardous Waste-

water Tanks with Overflow Protection
Fig. 143 Permanently Installed Wastewater Tank
8.5 Contaminated Waste

If contaminated with highly potent substances, solid wastes, such as e. g. seals/gaskets, films,
filters, cardboard, paper, etc., should be packed and disposed of. Packing may be carried out for
example using continuous liners. In this case, the waste is already enveloped with the film tube
during the removal via the airlock and thus no longer represents a hazard. These wastes must then
be fed into a controlled waste disposal procedure.
8.6 Post-Treatment of Wastes

All the waste types mentioned in this section cannot be fed into a “normal” waste disposal proce-
dure and must be collected in separate containers.
It is very important to ensure a clear and unmistakable labelling of the hazardous waste containers
and the waste itself in order to prevent the risk of exposure along the subsequent disposal chain
(e. g. transporter, waste disposal company). Sealing the containers significantly reduces the risk, but
it is not necessarily mandatory.
ID number: 1037317
Waste often has to be incinerated. The incineration of aqueous waste is generally very expensive,
so the amount of these wastes should be kept as low as possible (see section 8.4).
The collection containers for “dry” waste should be incinerated together with the residues in order
to avoid additional opening of the container and thus the associated risk.
9 Personnel

ID number: 1037317
ID number: 1037317
ISPE D/A/CH COP CON 9 Personnel
Containment Manual
9 Personnel
9.1 Training
Qualified personnel are essential for the production of pharmaceuticals. The personnel should not
only be able to master the production processes and fulfil all GMP requirements, but also be trained
in worker safety and occupational hygiene.
Such a training is part of risk management in the areas of occupational hygiene and safety at the
workplace. It is part of the organizational measures which take a front seat in the hierarchy of risk
management measures, right behind the technical measures for health protection and in front of the
use of personal protection articles.
In some countries, such as e. g. the USA, such trainings are regulated in detail (OSHA Hazard
Communication Standard, better known as “HazComm”).
Trainings should be carried out repeatedly and their implementation verified at regular intervals.
Safety Data Sheets (SDS)
The worker must know the pharmacological/toxicological effects of an exposure to the substances
being worked with and also be aware during which process steps particular risks of exposure may
occur. Safety data sheets (SDS) are important media for making such information available. SDSs
are standardized, but unfortunately in the case of development products often only a fraction of the
actually known information is provided in the SDS. For example, often information is missing
concerning the pharmacological effect, the intended effect caused by stimulation or inhibition of a
receptor, conclusions by analogy to similar but already better investigated molecules (read-across),
etc. If the material/substance is to be handled by a third party, then the contract giver is obliged to
provide all information necessary for the contract manufacturer to determine and establish adequate
worker protection measures. The contractor may not accept any contract if the information provided
on the substance to be handled and the equipment available do not permit safe working conditions
to be guaranteed.
Safety data sheets should not contain generic warnings stating that certain damaging effects could
possibly occur, especially if they arise only from the absence of information. Examples being “could
possibly have a sensitizing effect”, or “could possibly irritate the skin”, etc.).
Personal Protective Equipment (PPE)
If personal protective equipment is used e. g. for the case of failure of the technical protective
measures, or as a temporary measure until legally required technical protective installations have
been installed, then the personnel must be specially trained in the use of this personal protective
equipment. It is sometimes not possible to completely avoid the use of personal protective equip-
ment, although such personal protective equipment has been proven to be less effective than
technical measures. The reasons for this are often caused by the workers themselves: negligence,
lack of monitoring/supervision by the superiors, discomfort when wearing the protective equipment
(e. g. breathing resistance with respirators, perspiration in protective suits, obstructions to free vision
or free movement, communication problems when wearing ear protection, etc.). For this reason,
ID number: 1037317
training and information is decisive in motivating workers to correctly use their personal protective
equipment.

In addition, workers employed in the production of pharmaceuticals are required to have at least one
occupational medical examination when taking up work in this area in accordance with GMP regu-
lations. Following this, as a rule, additional or recurring medical and GMP-driven examinations are
carried out at longer intervals (every 1 to 3 years).
9 Personnel ISPE D/A/CH COP CON
Containment Manual
Short-term health problems such as colds, diarrhoea, and skin disorders are not picked up on by
examinations which are carried out at longer intervals. They may, however, be a reason why a
worker may temporarily not be assigned to a pharmaceutical production process. Every worker
must therefore be clearly aware which health problems he or she has the responsibility to report, in
order that their continued fitness for work is assessed by a medical professional.
9.2 Exposure Monitoring

The occupational hygiene monitoring of exposures at the workplace (see section 7) is, in most
situations, the most suitable means of monitoring exposure of a worker.
First and foremost, contamination of the room air at the workplace is measured, and additionally
surface wipe tests (swab tests) are often carried out. The weaknesses of this method include that
high exposures may be possible even at very low air contaminations e. g. when a substance is
absorbed in significant amounts through the skin or by swallowing.
The sampling strategy and the frequency of measurements as part of the conventional monitoring
of air and surface contaminations is discussed in section 7.
So-called biological monitoring may be used as an alternative or extension of these indirect

exposure measurements. This refers to the measurement of the API and its metabolites or their
biological effects in the worker’s biological material (blood, urine, breath). Instead of just measuring
the hazardous material or its metabolites, biological monitoring can also encompass the binding of
the hazardous material or its metabolites onto biological material (e. g. haemoglobin and/or DNA
adducts).
The advantage of this method is that hazardous materials and their metabolites or effects are
recorded no matter by what route they have entered the body (e. g. inhaled, absorbed through the
skin, swallowed, etc.).
Biological monitoring is sometimes invasive (blood sample required). It is complex, because

threshold values must be set that are relevant in relation to health risks. Unfortunately, biological
monitoring methods exist only for a limited number of substances.
To summarize, it can be stated that in the case of exposure monitoring, mostly air measurements
are carried out. The possibility for biological monitoring and swab tests should always be investi-
gated.

ID number: 1037317
10 Appendix

ID number: 1037317
ID number: 1037317
ISPE D/A/CH COP CON 10 Appendix
Containment Manual
10 Appendix
10.1 List of Abbreviations
Abbreviation Meaning
ACGHI American Conference of Governmental Industrial Hygienists

ADD Acceptable Daily Dose
ADE Acceptable Daily Exposure
ADI Allowable/Acceptable Daily Intake
ADME Absorption, Distribution, Metabolism and Excretion
AGS German Committee on Hazardous Substances (Ausschuss für Gefahrenstoffe)
AMG German Pharmaceuticals Law (Arzneimittelgesetz)
AMWHV German Law on Production of Pharmaceuticals and APIs (Arzneimittel- und
Wirkstoffherstellungsverordnung)
API Active Pharmaceutical Ingredient
ASHRAE American Society of Heating, Refrigeration & Air-Conditioning Eng.
ATEX Atmosphères Explosives/EU Directive on Potentially Explosive Atmospheres
CF Conversion Factor
CFR Code of Federal Regulation
CIP Cleaning in Place
CMR Carcinogenic, Mutagenic, toxic for Reproduction
CoP Community of Practice
COSSH Control of Substances Hazardous to Health Regulations (UK)
CPT Containment Performance Target
cRABS Closed RABS
DCS Double Chamber System or Drum Containment System
DEHS Diethylhexyl sebacate
DEL Design Exposure Limit
DFG
DIN
German Research Foundation (Deutsche Forschungsgemeinschaft)
German Industry Norm (Deutsche Industrie Norm)
DNA Desoxyribonucleic Acid
DOP
Mr.Dioctylphthalate
Bruno Henrique Santiago Lima
DQ
Design Qualification
EHS IDHealth
Environment number:& Safety 1037317
EMA European Medicines Agency
EN Downloaded
European Norm on: 1/15/19 11:37 AM
EPA Efficient Particular Air Filter
10 Appendix ISPE D/A/CH COP CON
Containment Manual
FAT Factory Acceptance Test

FDA Food and Drug Administration
FFU Fan Filter Unit
FIBC Flexible Intermediate Bulk Container
FMECA Failure Mode Effect & Criticality Analysis
FMEA Failure Mode Effect Analysis
FTA Fault Tree Analysis
GMP Good Manufacturing Practice
HAPI Highly Active Pharmaceutical Ingredient
HACCP Hazard Analysis and Critical Control Points
HAZOP Hazard Operability
HEPA High Efficiency Particular Air Filter
HHC Health Hazard Catecory
HPLC High Pressure Liquid Chromatographie
HP & LP High Pressure & Low Pressure
HSE Health Safety Environment oder Health and Safety Executive (UK)
HVAC Heating, Ventilation & Air Conditioning
IBC Intermediate Bulk Container
ICH International Conference on Harmonization
ILO International Labour Organization
INRS French National Research and Safety Institute (Institut National de Recherche
et de Sécurité)
IOM Institute of Occupational Medicine
IPC In Process Control
ISO International Organization for Standardization
ISPE International Society for Pharmaceutical Engineering
LC-MS Liquid Chromatography-Mass Spectrometry
LD50 Lethal Dose 50 (%)
LDPE
LOAEL
Low Density Polyethylene
Lowest Observed Adverse Effect Level
LOD Limit of Detection
LOEL
Lowest Observed Effect Level
LOQ
Belo Limit
Horizonte,
of Quantification
Minas Gerais,
MACO
ID number: 1037317
Maximum Allowable Carry-Over
MAK (German) Maximum Workplace Concentration (Maximale Arbeitsplatz
Downloaded
konzentration)on: 1/15/19 11:37 AM
MED Minimum Effect Dose
MPPS Most Penetration Particle Size
Containment Manual
MSDS Material Safety Data Sheet

MSW Microbiological Safety Cabinet
NIR Near Infrared Spectroscopy
NOAEL No Observed Adverse Effect Level
NOEL No Observed Effect Level
OEB Occupational Exposure Band
OEL Occupational Exposure Limit
OQ Operational Qualification
OSHA Occupational Safety & Health Administration
Pa Pascal
PAD Pharmacologically Active Dose
PAPR Powered Air Purifying Respirator
PAT Process Analytical Technology
PbOEL Performance-based Occupational Exposure Limit
PEL Permissible Exposure Limit
PHA Preliminary Hazard Analysis
PPE Personal Protective Equipment
PTFE Polytetrafluorethylene
PTS Powder Transfer System
PU Polyurethane
PVC Polyvinyl chloride
QC Quality Control
RA Risk Assessment/Risk Analysis
RABS Restricted Access Barrier System
REACH Registration, Evaluation and Authorisation and Restriction of Chemicals
RISK-MaPP Risk-based approach to Manufacturing Pharmaceutical Products
RTP Rapid Transfer Port
RTU Ready to Use
SAT This Document is licensed to
Site Acceptance Test
SDB Safety Data Sheet
SIP Mr.Sterilization
Brunoin Place Henrique Santiago Lima
SMEPAC Belo Horizonte,
Standardized Measurement ofMinas Gerais,
Equipment Particulate Airborne Concentration
SOP
ID number: 1037317
Standard Operational Procedure, Standard Operating Procedure
STEL Short Term Exposure Limit
STTWA Downloaded on: Average
Short Term Time Weighted 1/15/19 11:37 AM
TLV Threshold Limit Value
TRGS German Technical Rules for Hazardous Systems ( Technische Regeln für
Gefahrstoffe)
Containment Manual
TWA Time Weighted Average

ULPA Ultra Low Penetration Air Filter
URS User Requirement Specification
USP United States Pharmacopoea
UVV German Regulations for the Prevention of Accidents (Unfall-Verhütungs
vorschriften)
VDI Association of German Engineers (Verein Deutscher Ingenieure)
VDMA German Mechanical Engineering Industry Association (Verband Deutscher
Maschinen- und Anlagenbau)
VHP Vaporized Hydrogen Peroxide
VME German Association of the Metal and Electrical Industry (Verband der Metall-
und Elektroindustrie)
W Recovery Rate
WFI Water for Injection
WIP Washing in Place

ID number: 1037317
Containment Manual
10.2 Literature
[1] ISPE Baseline Guide Volume 1 – Active Pharmaceutical Ingredients
[2] ISPE Baseline Guide Volume 2 – Oral Solid Dosage Forms
[3] ISPE Baseline Guide: Risk-Based Manufacture of Pharmaceutical Products (Risk MaPP)
[4] ISPE Good Practice Guide – Assessing the Particulate Containment Performance of

Pharmaceutical Equipment (SMEPAC)

ID number: 1037317
Containment Manual
10.3 List of Figures and Tables
Figure Page Source
Title Sheet Cover SKAN AG, Allschwil CH

1 20 Bayer AG Leverkusen D
4 42 Hermann Waldner GmbH & Co KG, Wangen D
9 46 Pharma Containment Solutions, Edingen-Neckarhausen D
10 47 Glatt GmbH Process Technology, Binzen D
14 50 ARTEKA, Backnang-Waldrems D
17 51 Gebrüder Loedige Maschinenbau GmbH, Paderborn D
18 52 HOSOKAWA ALPINE Aktiensgesellschaft, Augsburg D
26
27
58
58
HOSOKAWA ALPINE Aktiensgesellschaft, Augsburg D
HOSOKAWA ALPINE Aktiensgesellschaft, Augsburg D
28
Mr.59Bruno Henrique
Fette Compacting GmbH, Schwarzenbek D
Santiago Lima
29 60 BMA Group, Braunschweig D
30
Belo
61
Pharma Maschinen Handelsges. mbH, Burgdorf D
31 62
ID number: 1037317
Pharma Maschinen Handelsges. mbH, Burgdorf D
32 62 Fette Compacting GmbH, Schwarzenbek D
33
Downloaded
64
on: 1/15/19 11:37 AM
Glatt GmbH Process Technology, Binzen D
Containment Manual
Figure Page Source
36 66 Uhlmann PAC Systeme GmbH & Co KG, Laupheim / SKAN AG,

Allschwil CH
37 68 Hüttlin GmbH / Bosch Packaging Technology Company, Schopfheim D
40 70 HOF Sonderanlagenbau GmbH, Lohra D
45 75 Hecht Technologie GmbH, Pfaffenhofen D
50 77 Novartis Pharma AG, Basel CH
62 This Document is licensed to
90 SKAN AG, Allschwil CH
63 91 SKAN AG, Allschwil CH
64 Mr.
92 Bruno Henrique
SKAN AG, Allschwil CH Santiago Lima
65 92
SKAN AG, Allschwil CH
ID number: 1037317
69 94 Castus GmbH & Co KG, Erolzheim D
70 a – c 94 Pharma Containment Solutions, Edingen-Neckarhausen D
Containment Manual
Figure Page Source

75 a + b 95 Pharma Containment Solutions, Edingen-Neckarhausen D
76 a + b 95 Pharma Containment Solutions, Edingen-Neckarhausen D
78 a – c 96 Hecht Technologie GmbH, Pfaffenhofen D
80 a – c 98 Matcon Group Ltd., Worcestershire, UK
82 a 99 Hecht Technologie GmbH, Pfaffenhofen D
82 b – g 100 Hecht Technologie GmbH, Pfaffenhofen D
85 a – c 103 Hecht Technologie GmbH, Pfaffenhofen D
92 a – d 109 Lugaia AG, Raron CH
93 110 La Calhene, Vendome Cedex F
94 111 HET Filter GmbH, Altenstadt D
98 This Document is licensed to
112 HET Filter GmbH, Altenstadt D
100 Mr.113Bruno Henrique Santiago
SKAN AG, Allschwil CH Lima
101 Belo
114 Horizonte, Minas
SKAN AG, Allschwil CH Gerais,
102 114
ID number: 1037317
SKAN AG, Allschwil CH
104
Downloaded
117
on: 1/15/19 11:37 AM
LS - tec, Reinach CH
105 118 LS - tec, Reinach CH
Containment Manual
Figure Page Source

114 125 Safebridge GmbH, Hamburg D
115 125 Safebridge GmbH, Hamburg D
116 125 Weiss GWE GmbH, Hude D
117 127 HS-Luftfilterbau GmbH, Kiel D

135
137 HET Filter GmbH, Altenstadt D
136 142 Adapted from Annals of American Conference of Governmental
Hygienists, Vol. 11
137 142 Adapted from Annals of American Conference of Governmental
Belo Horizonte,
Hygienists, Vol. 11 Minas Gerais,
138 143 ID number:
F. Hoffmann-La Roche1037317
AG, Arbeitshygienelabor
139 143 F. Hoffmann-La Roche AG, Arbeitshygienelabor
140 Downloaded
143 on: Roche
F. Hoffmann-La 1/15/19 11:37 AM
AG, Arbeitshygienelabor
141 143 F. Hoffmann-La Roche AG, Arbeitshygienelabor
Containment Manual
Figure Page Source

Table Page Source

2 142 F. Hoffmann-La Roche AG

ID number: 1037317
Containment Manual

ID number: 1037317
Containment Manual

ID number: 1037317

Containment Manual - ISPE PDF

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Containment Manual - ISPE PDF

Uploaded by

Copyright:

Available Formats

This Document is licensed to

Mr. Bruno Henrique Santiago Lima

Henryk Badack Vetter Pharma-Fertigung Ravensberg D

This Document is licensed to

4 Life-Cycle of Containment Solutions 33

5.1.5 Liquid Filling: Aseptic/Non-Aseptic 66

6.3.2 Handling of Air Filters 130

7 Occupational Hygiene/ Industrial Hygiene Validation 141

8 Cleaning/Waste Treatment 151

10 Appendix 163

This Document is licensed to

This Document is licensed to

1.2 Purpose and Objectives

1.3 Scope and Usage

▪▪ ISPE Baseline Guide Volume 1 – Active Pharmaceutical Ingredients [1],

▪▪ ISPE Baseline Guide Volume 2 – Oral Solid Dosage Forms [2],

▪▪ ISPE Baseline Guide Volume 7 – Risk-Based Manufacture of Pharmaceutical Products „Risk

▪▪ ISPE Good Practice Guide – Assessing the Particulate Containment Performance of Pharmaceu-

1.4 Structure of the Manual

This Document is licensed to

This Document is licensed to

2 Fundamental Considerations

2.1 The Term “Containment”

2.2 Primary and Secondary Containment

Downloaded on: 1/15/19 11:37 AM

Examples for secondary containment are:

▪▪ Adhesive floor mats to reduce inadvertent transfer of material via footwear.

2.3 Thresholds and Hazard Categories of Highly Potent Substances

The derivation of an OEL is made in several steps:

This Document is licensed to

• clinical data from the use of the medicine on humans,

• preclinical data e. g. data from tests on animals.

If needed a correction can be made according to the following formula if necessary:

Note also that correction/adjustment factors are applied as follows:

• F1 when data need to be extrapolated from animals to humans.

• F 2 where additionally the different sensitivities of the human sub-populations need to be

This Document is licensed to

Downloaded on: 1/15/19 11:37 AM

Category OEL Effect

G4 < 1 μg/m3 very high pharmacologic and toxic effect

G 3b < 10 μg/m3 high pharmacologic and toxic effect

G 3a < 100 μg/m3 medium pharmacologic and toxic effect

G2 < 1 000 μg/m3 low pharmacologic and toxic effect

G1 ≥ 1 000 μg/m3 very low pharmacologic and toxic effect

Fig. 1 Example for a classification system

2.4 Thresholds for Planning an Equipment

Mr. Bruno Henrique Santiago Lima

An example of a DEL system:

▪▪ Differentiation between short and long unit operations:

• long: duration more than 2 hours,

• short: duration less than 2 hours.

2.5 Regulatory and Legal Requirements

Risk = Hazard ∙ Exposure.

Mr. Bruno Henrique Santiago Lima

2.6 Basic Concepts

2.6.1 Building Concept

▪▪ Highly potent allergens such as beta-lactams e. g. penicillins or cephalosporins,

▪▪ Ectoparasiticides (e. g. substances for the treatment of lice).

The operating rooms must be depicted in a true-to-scale site plan.

2.6.2 Organizational Measures

2.6.3 Flow of Personnel

This Document is licensed to

This Document is licensed to

Fig. 4 Schematic Overview of a Mixing Equipment with Containment Isolator