3.

G Heating Ventilation Air Conditioning (HVAC)

Authors: Benno Weckerle, Dr. Ralph Gomez / Update 08
Here you will find answers to the following questions:

What is the meaning of the term "air technology"?

What kind of air technology systems exist?

What is the function of air filters?

How are air technology systems maintained?

3.G.1 Introduction
Pharmaceutical rules and specifications often contain very precise but also generally formulated
requirements of air conditioning technology, such as "temperature, humidity and ventilation of premises
should be adequate". This generally formulated requirement is partially substantiated in the
supplementary guideline of the EU GMP Guide for the manufacture of sterile products as it is in the FDA
GMP Regulations (21 CFR 211.46 (b),
chapter D.1.2).
The following chapters give a practical description of the extensive, and sometimes complex, field of air
conditioning technology in terms of the requirements that result from the pharmaceutical environment in
question.
The term air conditioning technology and its further sub-divisions are described in DIN 1946/Part 1.
Two basic types are distinguished by the terms
1. Room ventilation technology essential task of a ventilation system is to supply the desired room
conditions, such as temperature, humidity and cleanliness.
2. Process air conditioning technology. In contrast, the process air systems must guarantee the
required process parameters.
Both types are found and required in the pharmaceutical manufacturing sites.

Figure 3.G-1 shows the structure of the term "air conditioning technology"(extract from DIN 1946/Part 1)
with reference to deployment in the pharmaceutical manufacturing sites.

Figure 3.G-1 Structure of air conditioning technology

1. Belong to the equipment in the pharmaceutical manufacturing sites, e.g. fluid bed spray
granulation, drying processes, coating processes
2. Both types of ventilation systems "with"and "without"ventilation functions, as well as a
combination of both are found in the pharmaceutical manufacturing sites
3. Not represented in the pharmaceutical manufacturing sites

In the air conditioning technology structure, a distinction is made between ventilation systems with and
without ventilation functions. The term ventilation function means that the air in the room is exchanged
with external air. The further sub-structure shows the number of thermodynamic air handling functions
with which the ventilation system is equipped. The thermodynamic air handling functions shown in
Figure 3.G-2 apply for the preparation of the inlet air: heating, cooling, humidifying and dehumidifying.

Two or three Four

air Recirculating

Air
conditioners

Partial air

Recirculating
air partial air
conditioners

None or
one

conditioner

Recirculating
facilities

Number of thermodynamic air handling

functions

facilities

Classification
of room
ventilation
systems

Ventilation

Figure 3.G-2 Classification of ventilation systems

The terms for classification of ventilation systems do not provide any information on the filtering of the
inlet air.
The next chapters deal exclusively with room ventilation facilities. No detail is given of the engineeringrelated planning of ventilation systems, but instead the focus is placed on the fundamental design,
planning, solution options and implementation in terms of the pharmaceutical requirements.

3.G.2 Room ventilation systems

The room ventilation systems are designated according to the available thermodynamic air handling
functions in a ventilation system (acc. to DIN 1946 / Part 1, see
Figure 3.G-2 classification of ventilation systems).
The respective design and structure of the ventilation systems results from the requirements and
conditions made of the ventilation system (see
chapter 3.G.4 Principles for the design and planning of air conditioning ventilation systems).
The following criteria can play a role in the selection of the system to be used:

Influence of outside air

Climatic conditions of site

Operational costs of the different systems, especially the costs for energy consumption: current,
heat, cold (cooling, dehumidification) and humidification

Cleanliness requirements

Flexibility

In pharmaceutical manufacturing, essentially the following ventilation systems are used.

3.G.2.1 Pure (100%) external air conditioning system

The inlet air to the rooms always consists of 100% external air. The external air is prepared in the
ventilation system according to the defined conditions (temperature, humidity, purity). With a pure
external air facility, impurities/contamination cannot enter the inlet air system via the exhaust air system.
When using a heat recovery system, it must be ensured that the two systems cannot be connected via the
heat recovery components (
Figure 3.G-3).
Pure external air conditioning systems are used with the following conditions:

Supply of different production areas through a joint ventilation system

The exhaust air from the rooms is so highly contaminated with impurities that the safe elimination
of impurities can not be assured by the cleaning/filter phases of the ventilation system.

Flexibility is required, i.e. at any time, a manufacturing site for a different product group with other
requirements can be supplied without a risk of cross-contamination.
Figure 3.G-3 Diagram of a pure external air plant

3.G.2.2 Central recirculating air/mixed air conditioning system

The inlet air to the rooms consists of some external air and some recirculating air. The share of "external
air" and "recirculating air"can be fixed or can be variable according to the external temperature.
It is important that the amount of external air be properly adjusted to accommodate the number of people
working in the manufacturing site (
Figure 3.G-4).
Central recirculating air/mixed air conditioning systems are used with the following conditions:

Supply of one production area (dedicated equipment).

The concentration of impurities in the exhaust air from the rooms is low enough that the safe
elimination of the impurities is achieved via the cleaning/filter stages of the air technology system.

Direct heat recovery without additional heat exchanger (low investment costs).

No flexibility - i.e. a manufacturing site for a different product group with other requirements cannot
be supplied without a risk of cross-contamination
Figure 3.G-4 Diagram of a central recirculating air/mixed air plant

3.G.2.3 Decentralized recirculating air/mixed air conditioning system with

central external air preparation
The air supply and exhaust air of a room or a zone is conveyed via a recirculating air facility. Conveying
centrally-prepared external air guarantees the required external air share for the personnel in the rooms (
Figure 3.G-5).

Figure 3.G-5 Decentralized recirculating air/mixed air conditioning system

with central external air preparation
The

recirculating air facility is usually fitted with a condenser and a filter stage. Decentralized recirculating
air/mixed air facilities with central external air preparation are used with the following conditions:

Supply of different production areas through a joint external air preparation system

The concentration of impurities in the exhaust air from the rooms is so low that safe elimination of
the impurities is achieved via the cleaning/filter stages of the decentralized recirculating air facility.

Flexibility, i.e. a manufacturing site for another product group with other requirement can be
supplied at any time, if the central external air preparation is carried out with a "pure external air
plant".

3.G.2.4 Pure recirculating air conditioning system

The air supply and exhaust air of a room or a zone is conveyed via a recirculating air facility. No prepared
external air is supplied. The pure recirculating air facility is therefore only used for areas, which are not
permanently staffed and where the inlet of external air could influence the air quality (
Figure 3.G-6). Typical applications are partially high-quality clean room zones in a clean room, e.g. zones of
cleanliness class A in a sterile room, LF work benches.
Figure 3.G-6 Pure recirculating air conditioning system

3.G.2.5 Systems for tempering and volume flow regulation

The following two systems have proven their worth in practice for tempering and volume flow regulation:

Single duct system: temperature regulation takes place either by room or by zone via postheating registers or aftercoolers. The air currents (air volume) are today usually configured or
regulated with volume current regulators. With constant air currents, a very simple setting can be
made via throttles such as flaps and perforated plates (

Figure 3.G-7).

Figure 3.G-7 Room supply with a single duct system

Dual duct system: after the central air preparation facility, the inlet air is split across two
differently tempered air supply ducts. The air in the warm duct is heated to a temperature of 25 to
35 C, while the air in the cold duct is cooled to 15 to 18 C, for example. Before a room or zone,
the two air flows are mixed in a blending box according to the required room temperature and heat
burden, and blown in as inlet air. With the blending boxes, constant air currents (air volume) or
variable volumes can be set (
Figure 3.G-8).

Figure 3.G-8 Room supply with a dual duct system

3.G.2.6 Control-systems of the air volume flows

In principle, a distinction is made between a constant or variable inlet and exhaust air current supply for
individual rooms, zones or areas. The two supply strategies differ as shown in
Figure 3.G-9.
Figure 3.G-9 Comparison of volume current systems
Constant air volume flow
A fixed volume current is set via a
constant volume current regulator,
blending box, flap or other throttle.
With a single duct facility,
temperature regulation takes place
either by room or by zone via postheating registers or aftercoolers.
Advantages:

Variable air volume flow

Depending on the heat in the room or in a zone and/or the
activity, the air volume currents (inlet and exhaust air) can be
raised from an initial value to a maximum value, e.g. via the
temperature regulator. With decreasing heat and/or activity, the
air currents are reduced to the initial value.

Advantages:

Simple design

Low energy consumption/costs

Steadily working systems

More flexible system, e.g. in terms of highly changeable

heat burdens

External influences can be ruled out, e.g. by pressure

regulation due to changing wind pressure.

Disadvantages:

Disadvantages:

High energy consumption/costs

More complex design

Cannot react to influences, or

only marginally

Higher level of automation required

3.G.2.7 Utilities for the operation of room ventilation systems

Different kinds of energies (and utilities) are required to operate ventilation systems, in order to convey the
air, filter it and enable thermodynamic air handling functions such as heating, cooling, dehumidifying and
humidifying. Energies that are used for heating, cooling and dehumidifying do not usually have any direct
contact with the air to be prepared. The air is passed through heat exchangers, which are equipped with
lamellas on the air side. The energy supply is via pipes that are connected to the lamellas.
The essential energies (and utilities) used in ventilation systems are described in
Figure 3.G-10.
Figure 3.G-10 Energies and utilities for ventilation functions
Physical or thermodynamic functions

Type of energy or utility

Air delivery

Current

Hot water (pumping warm water, e.g. 80/60 C)

Steam

Current

Cooling water (e.g. 6/12 C)

Coolant

Water

Steam

Heating

Cooling/dehumidifying

Humidifying

3.G.3 Filters
To attain the required air quality and conditions in the premises of a pharmaceutical manufacturing site,
different standard components are used to configure an air technology system.
The required purity of the air in the premises can only be achieved with effective cleaning of the external
air or recirculating air. This requires a suitable, correctly designed filter.

Air filters are components through which particles and gaseous impurities are filtered and separated from
the air. The ambient air is penetrated by substances of different particle sizes and materials. This mixture
of ingredients must be cleaned by suitable filters so that the required cleanliness conditions are complied
with in a manufacturing site.
Separation in the air filters (filter medium) is based on different physical effects (see
Figure 3.G-11).

Figure 3.G-11 Physical separation effects at

the individual fibres of a filter medium

The most important separation effects are

Diffusion effect: the diffusion effect is a consequence of Brownian molecular movement and is
therefore only effective for very small particles. The molecular movement causes a diffuse
movement of the particle along a virtual streamline. It is separated at the fiber if it remains
sufficiently close to the fiber for a long enough time.

Inertness effect: the inertness effect causes separation at the fibers, if the particle is of a
particular size and thus cannot follow the course of the streamline.

Blocking effect: the blocking effect always occurs, if a particle is on a streamline whose distance
from the fiber during circulation is less than half the particle diameter.

Sieve effect: the sieve effect only occurs for a particle whose diameter is greater than the free
cross-section between the fibers (pore width).

The different filter qualities are split into coarse, fine and suspended matter filters according to the
separation capacity of the different particles. This division is based on standardized testing procedures.
Today, following many intermediate steps, the following are two valid European standards for air filters

DIN EN 779 Particle air filter for general ventilation

DIN EN 1822-1 Suspended matter filter (HEPA and ULPA) are the specifications and testing bases for
all filter manufacturers.

Figure 3.G-12 Structure of the air filter in accordance with DIN 24183 (E) Part 1

3.G.3.1 Particle air filter

The particle air filters are classed in "coarse (G1 to G4)"and "fine (F5 to F 6)" filter groups in accordance
with DIN EN 779 (see
Figure 3.G-13).
Figure 3.G-13 Classification of particle filters according to DIN EN 779
Initial effectiveness (EA)

EA < 20%

EA 20%

Characteristics

Average separation rate Am (%)

Average effectiveness Em (%)

Filter group

Filter class

Coarse (G)

G1

Class limits
Am < 65

G2

5 Am < 80

G3

80 Am < 90

Fine (F)

G4

80 Am

F5

40 Em < 60

F6

60 Em < 80

F7

80 Em < 90

F8

90 Em < 95

F9

95 Em

Am = Average separation rate compared with synthetic dust

Em = Average effectiveness compared with atmospheric dust
For pharmaceutical manufacturing sites, the coarse filters are irrelevant as the separating power of these
filters is too low to achieve the required purity; total effectiveness of the filter >95 %. This total
effectiveness can only be achieved with fine filters in the 1st and 2nd filter stage of air technology
equipment.
The following combinations of filter classes are used today for two filter stages in series:

1st filter stage F 6 or F 7

2nd filter stage F 9

With this filter combination, the following targets are achieved:

Total effectiveness > 95%

High period of use of the filter

Manageable energy costs

With all mechanical filters, it must be taken into account that the separation power is not constant, but
changes due to the following factors:

Fluctuating dust content of the external air: due to the season (e.g. pollen in spring) and
environment (e.g. emissions of hazardous substances from neighboring plants), the dust content of
the external air fluctuates.

Velocity at which the air passes through the filter medium: with a reduced volume flow in relation to
the test volume flow, the separation rate tends to increase.

Filter cakes: with the increasing contamination (build-up of a filter cake) of the filter, the separation
rate increases due to the additional filtration through the collected dust.

Air humidity: in hygiene areas, the air filter should be prevented from dropping below the dewpoint,
as bacteria and fungus growth is encouraged near the dewpoint. The relative humidity of the air
flushing through should therefore not exceed a maximum value of 95 %.

The filter media used consist of fiberglass or synthetic-organic fibers, which are then connected thermally
or chemically with binding agents. The following models are generally used (see
Figure 3.G-14):

Filter mats Filter classes G1 to F 6

Conveyor belt filter Filter classes G 1 to F 5

Pocket filter Filter classes G1 to F 9

Cassette filter Filter classes F 5 to F 9 (rigid filter)

Figure 3.G-14 Models of air filters

EN
4/9

Figure 3.G-15
Comparison of DIN
779 and Eurovent

Today, the separation rate or effectiveness of the particle air filters is determined as a percentage in
comparison with "atmospheric dust"or "synthetic dust", without producing a reference to a particle size.
The first investigations and standardization activities aim to determine a fractional separation rate for a
defined particle size for the comparison of the efficiency of a particle air filter.
The diagram (see
Figure 3.G-16) shows a comparison of the separation rate (%) for the different particle sizes by pocket
filters with different filter classes. At present, the fractional separation rate should be calculated according
to the Eurovent draft standard with a particle size of 0.4 m.

Figure 3.G-16 Comparison of fractional separation rates of pocket filters

3.G.3.2 Suspended matter filter - HEPA-Filter

For clean rooms with defined particle counts in the room air, usually a 3rd filter stage must be provided in
addition to the two particle air filter stages. As the 3rd filter stage, the suspended matter filter should be
fitted as near as possible to the end of the room, i.e. just before the entry of the inlet air into the clean
room.
With suspended matter filters, dust, suspended matter and aerosols can be separated in a range up to 0.1
m.
For the specification of the suspended matter filter, the different national standards were transferred
into a European standard "DIN EN 1822/T 1-5" (
Figure 3.G-17).

Figure 3.G-17 DIN EN 1822 Suspended matter filter (HEPA and ULPA)

DIN EN 1822 Suspended matter filter (HEPA and ULPA)

Part

Title

Classification, performance test, labeling

Status/Valid

July 1998

Aerosol generation, measuring instruments, particle count statistic

July 1998

Check of the planned filter medium

July 1998

Leak test on the filter element (scan procedure)

Open

Separation rate test of the filter element

Open

According to the above-mentioned DIN standard, suspended matter filters have the filter classes illustrated
in
Figure 3.G-18 with the associated filtration performances.

Figure 3.G-18 Classification of HEPA and ULPA filters according to their filtration performance in
accordance with DIN EN 1822-1)

Integral value
Filter
class

Separation
rate (%)

Local value

Forward
rate (%)

Separation rate
(%)

Forward
rate (%)

H10

85

15

H11

95

H12

99.5

0.5

H13

99.95

0.05

99.75

0.25

H14

99.995

0.005

99.975

0.025

U 15

99.999 5

0.000 5

99.997 5

0.002 5

U 16

99.999 95

0.000 05

99.999 75

0.000 25

U 17

99.999 995

0.000 005

99. 999 9

0.000 1

HEPA filter (H) => High Efficiency Particulate Air Filter

ULPA filter (U) => Ultra Low Penetration Air Filter

To assess the suspended matter filters, a testing procedure was defined in DIN EN 1882 in which the
separation rate is determined in the separation rate minimum. The physical basis is the characteristic
minimum curve, which describes the separation behavior of fiber filters and thus also of suspended matter
filters (see
Figure 3.G-19).

Figure 3.G-19 Characteristic minimum curve for describing

the separation behavior of fiber filters

The minimum lies in the transition area between stochastic movement (diffusion) through Brownian
molecular movement and inertness effect as the determining separation mechanisms.
The position of the suspended matter filter's separation rate minimum, both in terms of the percentage
separate rate and also of the particle size with the highest penetration, depends on the velocity of the air
flow through the filter medium. The particle size with the highest penetration for a defined filter medium
flow velocity is called the Most Penetration Particle Size (MPPS = separation rate minimum).
Through the connection between the filter medium flow velocity and separation performance, the
separation performance of a suspended matter filter can be increased by reducing the medium velocity
(see
Figure 3.G-20).
Figure 3.G-20 Two minimum curves of a suspended matter filter

medium at different filter medium flow velocities

The determination and assignment of the individual suspended matter filters to the filter classes is carried
out in accordance with DIN EN 1822. The suspended matter filters of classes up to H 14 can be tested with
the so-called oil strand test. Starting with filter class U15, a leak detection of the particle count method
must be carried out, although it is advisable to perform the particle count method starting with filter class
H 13.
Leakage test
With the oil strand test a leak is visually detected. The filter element is acted upon by a high concentration
paraffin cloud at the raw air side and a tester check, if identifiable oil strands are present at the pure air
side. Every identified oil strand indicates the position of a leak (
Figure 3.G-21).
Figure 3.G-21 Schematic test structure for carrying out the
leakage test on LF units

to enlarge, click here!

The leak detection and separation rate determination using the particle method has the following
advantages:

High precision of the measurements

Determination of the total separation rate in the separation rate minimum

Determination of the local separation rate

Determination of leak positions

For the particle method, DIN EN 1822 prescribes the following procedure:

Determination of the Minimum Penetration Particle Size (MPPS) with a defined filter medium flow
velocity on a flat filter medium

Fully scan the finished filter element with specified volume flow using MPPS particles

Calculation of the integral and local separation rates

Classification of the filter in the corresponding filter class

The test methods described in DIN EN 1822 can be implemented by the filter manufacturers with
corresponding test benches. The tests cannot usually be fully implemented when testing fitted suspended
matter filters.
The test structure shown in
Figure 3.G-21 is possible when using the particle count method for fitted suspended matter filters:

The test aerosol is applied to the suspended matter filter at the raw air side of the filter as follows.

LF unit: the aerosol is applied via the ventilator aspiration or the aspiration channel.

Suspended matter filter air outlet: the aerosol is applied via a connection fitted to the raw air side of
the inlet air duct.

The particle concentration of at least 106/ft3 particles of 0.3 m to be applied on the raw air side exceeds
the count range of the particle counter. Therefore, the aerosol concentration is diluted before the particle
counter by a dilution stage of 1:10 or 1:100. Each individual suspended matter filter is then tested for
leaks by slowly and completely passing over the entire filter surface on the raw air side with the particle
counter's isokinetic sensor.
A leak is defined as follows: a leak is present, if the permissible penetration rate of the suspended matter
filter is exceeded or its permissible separation rate is undershot. A distinction is made between integral
and local leaks.
An integral leak is present, if the ratio of the particle concentration measured over the entire filter at the
inlet and exhaust side is not achieved in accordance with the separation rate or penetration rate
prescribed in the filter class.
A local leak is present, if the ratio of the locally measured particle concentration at the inlet and exhaust
side is not achieved in accordance with the separation rate or penetration rate prescribed in the filter
class.
Designs
The filter media of suspended matter filters have a relatively high pressure differential. In order to
accommodate as many filter surfaces as possible on the limited designed space, the filter medium is
folded (see

Figure 3.G-22 and

Figure 3.G-23).
Figure 3.G-22 Separator technique

Figure 3.G-23 Strand design

!

The older type of fold is the separator technique. The filter medium is folded lengthwise and widthwise
alternately and a separator of corrugated aluminum is inserted in the resulting chambers, which prevents
the filter medium from coming into contact with itself and thus creating an unusable filter surface. A
disadvantage of the corrugated and sharp-edged aluminum separators is that they can tear the filter
medium and create holes in it. This hazard applies during production, transport, fitting and in current
operation through pulsing air currents.
The further development of the folding technique led to the strand design. The strand design technique
allows the filter medium to fold with narrower spaces than the separator design. Thus, a greater filter
surface can be realized in a suspended matter filter with a strand design of the same dimensions. The
contact points of the spacers on the filter medium are significantly lower with the strand design than with
the separator design
This technique results in the following advantages for suspended matter filters with a strand design:

No mechanical stress on the filter medium through metal separators

Lower height with the same dimensions and filter surface

Lower pressure losses.

3.G.3.3 Air Filtration in the FDA's Sterile Drug Products Produced by

Aseptic Processing guideline
The Sterile Drug Products Produced by Aseptic Processing guideline gives FDA's recommendations on air
filtration in aseptic processing facilities.

Compressed air, nitrogen, and carbon dioxide are commonly used in cleanrooms. These, and all other
utilized gases, must be of the requisite purity and after filtration their microbiological quality and particle
content should be at least equal to but preferably superior to the air into which the gas is introduced.
Membrane Filters: membrane filters are capable of generating sterile compressed gases which can be
used in processes involving sterile materials, such as components and equipment. The FDA guideline
recommends "that sterile membrane filters be used for autoclave air lines, lyophilizer vacuum breaks, and
tanks containing sterilized materials. Sterilized holding tanks and any contained liquids should be held
under positive pressure or appropriately sealed to prevent microbial contamination. Safeguards should be
in place to prevent a pressure change that can result in contamination due to back flow of nonsterile air or
liquid".
Any moisture on gas filters may cause blockage and permit the growth of microorganisms. Therefore,
precautions should be taken to assure that these filters are dry. Employing hydrophobic filters and, if
possible, applying heat to the filters averts difficulties with moisture residues. The guideline recommends
that any filters that are used to maintain sterility that can affect product be integrity tested at installation
and periodically during its lifetime. The filters should also be tested after any activities that may
compromise the filter. Any failures during integrity testing must be investigated. Also, filters should be
replaced at scheduled intervals.
High-Efficiency Particulate Air (HEPA) Filters: in order to insure aseptic conditions, the integrity of HEPA
filters (
chapter 3.G.3.2 Suspended matter filter - HEPA-Filter) must be preserved. One way of verifying the
integrity of the filters is to perform leak testing at installation and periodically, such as twice per year in
the aseptic processing room. Leak testing should also be performed, when the air quality is found to be
unacceptable, when renovations have taken place in the area, or an investigation is conducted due to a
media fill or product sterility failure. Filters in dry heat depyrogenation tunnels and ovens should also be
leak tested. The guideline allows for the use of alternate methods for the testing of HEPA filters in the hot
zones of depyrogenation tunnels and ovens. However, a justification for the use of alternate procedures
must be provided.
Typical aerosols used for leak testing include dioctylphthalate (DOP) and poly-alpha-olefin (PAO). Caution
has to be used when choosing alternate aerosols, since some increase the risk of microbial contamination
of the environment. Therefore, it is imperative that these alternate aerosols be tested to determine if they
support microbial growth.
Efficiency testing differs from filter leak testing in that the former is designed to establish the filter rating
while the latter detects leaks from the filter media, frame or seal. The efficiency test is conducted by using
a monodispersed aerosol of 0.3 micron sized particles and measuring downstream. The obtained
measurements are an average over the filter surface. Efficiency tests are not designed to detect filter
leaks. An acceptable filter retains at least 99.97 percent of particulates greater than 0.3 m in diameter.
The leak test is conducted by using a polydispersed aerosol of particles with a light-scattering mean
droplet diameter between 0.3 mm and 1 micron, but which includes a sufficient number of particles at
approximately 0.3 mm. An aerosol composed of known concentration and particle size is introduced
upstream of the filter. The filter is scanned with a probe and the leakage is calculated as a percent of the
upstream challenge. The testing procedure and results obtained should be documented in writing. A result
of 0.01 percent of the upstream challenge is considered as a significant leak and requires either the
replacement of the HEPA filter or, when appropriate, repair. In the event of a repair, its success should be
confirmed by performing a retest of the leak test.

In addition to leak testing, filter performance must also be monitored by measuring other filter attributes,
such as uniformity of velocity across the filter and relative to adjacent filters. HEPA filters should be
replaced when nonuniformity of air velocity across an area of the filter is detected. Nonuniformity of air
velocity across an area of the filter will adversely affect airflow patterns. If this occurs, the HEPA filter
should be replaced. The principles discussed in this section of the guideline are also appropriate for use
with ULPA filters.
3.G.4 Principles for the design and planning of air
conditioning ventilation systems
When planning an air technology system, the principles must be clearly and unambiguously defined. For
the ventilation systems to be designed and planned for a pharmaceutical manufacturing site, the external
conditions of the site (see
Figure 3.G-24), the requirements of the premises (see
Figure 3.G-25), the production factors that influence the room climate (see
Figure 3.G-26) and the layout-dependent requirements (see
Figure 3.G-27) must be known. Only if all conditions and requirements are known, can an optimal
ventilation system be designed and planned. The data should be summarized in a room log, which must be
available to every person involved in the planning. (See
chapter 3.A.6 Room book and layout.)
Figure 3.G-24 External conditions of the site
External conditions of the site
External temperature

Specified values for the minimum and maximum external temperature.

Air humidity

Minimum and maximum values

Sound limits

Noise technical instructions, day/night limits (compliance with sound limits for
the neighborhood)

Emissions of harmful
substances

Air limits technical instructions (dust, solvent, odors, etc.)

Altitude

Important, as the key fields of pumps and ventilators, for example, relate to
the standard conditions.

Cardinal points

Orientation of the building

Wind directions

Main wind direction, wind speeds

Figure 3.G-25 Requirements of premises

Requirements of premises

Purity

Cleanliness class of the rooms in accordance with the EU GMP Guide, FDA Drug Products Produced
by Aseptic Processing guideline, CFR (FDA), DIN EN ISO 14644-1, VDI 2083.

Special data on the required laminar ranges (cleanliness class A). Define size and position in the
layout.

Pressure conditions
compared with
bordering rooms/areas

Negative/positive pressure (e.g. 12.5 PA positive pressure between cleanliness classes)

Alarm values, alert values

With defined pressure conditions, it must be defined how the pressure is built up/relieved over
different resistances (e.g. doors). Doors may have to be locked against each other.

Air flow direction

Define overflow direction per room (in, out or neutral)

Temperature

Temperature range (e.g. 19-25 C), required temperature value (e.g. 22 C), summer compensation,
tolerance (e.g. 2 ), alarm values, separate values for non-working time

Humidity

Humidity range (e.g. 40- 65 % r.h.), required dehumidification and/or humidification value,
tolerance, alarm values, separate values for non-working time

Monitoring devices

Particle concentrations

Temperatures

Air humidity

Pressure conditions

Air flow direction

Noise

e.g. sound pressure level for production rooms

50-70 dB (A)

Figure 3.G-26 Usage-dependent requirements

Usage-dependent requirements

Manufacturing type

Solid, liquid, sterile production, etc.

Hazard potentials of production

materials or of the drug(s)

Toxicity, MAC values, radioactivity, biological substances

(viruses, bacteria)

Production times

1, 2, 3 shift operation

Reliability

Redundancy required: yes/no

(if yes e.g. 100 % split to 2 x 50% 50%
still available if a system fails, 2 x 70% 70%
still available if a system fails, 3 x 50% 100%
still available if a system fails, etc.)

Recirculating air possible

Yes/no (increase of harmful substance concentration

possible, cross-contamination, validation possible, etc.)

Special process air facilities for

process equipment

Required (inlet air and/or exhaust air) e.g. coating

facilities, granulating facilities etc.

Sources of harmful
substances that have to be recorded

Dust

Solvent

Disinfectant

EX - zone classification of premises for production and

engineering areas and for equipment

EX - protection requirements

Heat sources

Persons

Number/activity

Lighting

Power input, number

Production equipment

e.g. tablet press, coating facilities, filling equipment,

autoclave, freeze-drying facility, etc.

Containers, pipes

Uninsulated, hot areas

Sterilization processes

Hot surfaces, emanating steam, etc.

External heat loads

Through windows, walls, ceilings

Simultaneity and duration of

processes

Important point to determine the "peak load"

Type of clothing that must be worn by the personnel

Particularly important for temperature definitions, if clean

room clothing is worn.

Staff clothing

Figure 3.G-27 Layout-dependent requirements/dimensions

Layout-dependent requirements/dimensions

Number of rooms

Main usage areas, auxiliary usage areas, traffic areas

Size of the rooms

Room areas in m or ft2, length and width

Height of the rooms

Room height in m or ft

Definitions for the

facilities
infrastructure

Possibilities for the routing of supply and removal streets

Definition of the philosophy in terms of the operation and maintenance of

air technology components (e.g. volume flow regulator, filter change from
pure to impure area).

Technology areas

Function areas, premises for the assembly of the air technology systems

Evaluation of the principles

Using the formulated requirements and conditions, an air volume table can be compiled in relation to the
rooms. The air volume table can be used to summarize all important data for the air technology system.
Figure 3.G-31 to
Figure 3.G-32 and
Figure 3.G-28 contain two examples of a summary of the most important data, including

General room data (room number, room name, area, height, volume etc.)

Volume of inlet air, exhaust air, overflow air (min./max. values; per room)

Air exchange (min./max. values; per room)

Air volumes of special air technology systems

Figure 3.G-28 Air volume table

to enlarge, click here!

The second example shows the determination of the heat load in the room. This diagram is shown at the
end of chapter 3.H-5 (
Figure 3.G-31 to
Figure 3.G-32).
3.G.5 Design criteria for the ventilation of premises
The design of a room ventilation system for supplying the rooms is not specified accurately in the various
GMP specifications and rules. The ventilation systems are to be designed so that adequate ventilation is
achieved.
The actual implementation of the requirements for supplying the rooms with air means dealing with the
following design criteria:

How is the inlet air brought into the room? Inlet air flow pattern

How many filter stages are required and with what quality?
Air filter/stages/air filter quality

Room conditions Temperature/humidity/summer compensation

What air change is required? Air change

How should the exhaust air be aspirated from the room? Exhaust air flow pattern

Are pressure differences or defined flows required between rooms or areas?

Room pressures/pressure stages/defined flows

How are locks designed? Door locking/air flow pattern

Figure 3.G-29 lists the basic design features with solution approaches for the design of the room supply.
The data does not relate to the design of air technology equipment.
3.G.5.1 Air technology design of a sterile room with negative
pressure plenum
A sterile room with a negative pressure plenum has the following construction principles (see
Figure 3.G-29).
Above the sterile room, a second room is created, which is connected to the sterile room via recirculating
air ducts. The LF areas (filter fan units) are integrated in the ceiling between the sterile room and plenum.
The filter fan units convey the air in the circuit between the sterile room and the plenum. The air is
aspirated from the sterile room via aspiration points near the floor and conveyed to the plenum. In
addition, the required fresh air is brought into the plenum as inlet air. The recirculating air and the inlet air
are brought into the sterile room as initial air. Further inlet air can be brought in via area B through
suspended matter filter air outlets. The excess air is allowed to flow into bordering areas, e.g. locks,
engineering areas of autoclaves, etc. The overflow openings with constant air volumes are designed as
gratings. Overflow openings can be fitted with adjustable flaps to control the pressure.

The diagram shows the main possibility of how a sterile room can be designed with a negative pressure
plenum. Details about the technical solutions for all listed components can be found.
Figure 3.G-29 Sterile room with negative pressure plenum

to enlarge, click here!

3.G.5.2 Pressure stages and design of the pressure

differential
measurement for a sterile area
In accordance with the requirements, a pressure
differential is realized between each cleanliness class. If
each cleanliness area is measured at a reference point,
this results in a clearly traceable record, e.g. with a line
writer as the lines of the individual cleanliness areas are
always offset by the pressure differential. As the
individual traces must be offset and parallel, it is easy to
recognize, if the cleanliness areas have always been in
the prescribed pressure area.
The diagram (see
Figure 3.G-30) shows how the individual pressure differentials are always measured in relation to a
reference point. The alarms are determined from the differences between the cleanliness classes.
For example, the following values could result from the individual pressure differential measurements:

PDIS 1: 12.5 Pa (pharmaceutical area/D area)

PDIS 2: 25 Pa (pharmaceutical area/C area)

PDIS 3: 32.5 Pa (pharmaceutical area/lock to sterile room)

PDIS 4: 37.5 Pa (pharmaceutical area/sterile room)

Figure 3.G-30 Pressure stages and design of the pressure differential measurement for a sterile area

to enlarge, click here!

3.G.5.3 Pressure Differentials in the FDA's Sterile

Drug Products
Produced by Aseptic Processing guideline
The FDA's Sterile Drug Products Produced by Aseptic Processing guideline addresses clean area separation
and the maintenance of positive pressure differentials from higher to lower cleanliness rooms (section
IV.C). The FDA's recommendation is to ensure a positive pressure differential of at least 10 to 15 Pa
between rooms of different classifications that are adjacent to one another and with doors closed. If the
doors are open the outward air flow should be sufficient to keep contamination from entering the room. It
is important to establish a time limit for how long the door can remain ajar or open.
For adjacent rooms that have the same classification, the guideline states that "maintaining a pressure
differential (with doors closed) between the aseptic processing room and these adjacent rooms can provide
beneficial separation". If the aseptic processing room is adjacent to an unclassified room, then the
guideline recommends maintaining an over pressure from the aseptic processing room of at least 12.5 Pa.
If the pressure differential falls below the recommended level then the environmental quality in the aseptic
room may be compromised. It is then important to restore the air quality of the aseptic processing room
and confirm that it meets the requirements. The guideline further recommends that pressure differentials
should be continuously monitored and recorded and any alarms that signify a deviation from the
established range should be documented and investigated.
Air change rate is also important for cleanrooms. For Class 100,000 rooms, FDA recommends 20 air
changes per hour. For Class 10,000 and Class 100 areas, much higher air change rates are needed.
Finally, a reliable facility monitoring system is critical to quickly detect atypical changes that can affect the
environment and assist in the restoration of the appropriate operating conditions to qualified levels before
action levels are reached.
Ventilation design criteria for GMP-conform production rooms
Figure 3.G-31 Calculation of cooling loads

to enlarge, click here!

Figure 3.G-32 Ventilation and air-conditioning design - criteria for GMP-compliant production rooms

to enlarge, click here!

to

enlarge, click here!

to enlarge, click here!

Figure 3.G-32 Ventilation and air-conditioning design - criteria for GMP-compliant production rooms

to enlarge, click here!

to enlarge, click here!

For operation, maintenance is an essential factor for preserving safe, fully functional and economic
operation in terms of the required statuses (chapter 4.H Maintenance). FDA's Sterile Drug Products
Produced by Aseptic Processing guideline emphasizes maintenance as an important criterion to insure the
proper functioning of air ventilation systems. In section IV.A, the guideline states, "...even successfully
qualified systems can be compromised by poor operational, maintenance, or personnel practices".
The following are targets for air technology systems with planned and regularly executed maintenance
measures (
Figure 3.G-34):

Guaranteeing and complying with physical parameters, such as temperature, humidity, pressure
differences, etc.

Guaranteeing a hygienic operation (purity, particle count etc.)

Ensuring and increasing availability

Guaranteeing economic operation (low energy costs)

Identifying and eliminating weaknesses

Maintaining the value of the system (longer life)

Figure 3.G-34 Maintenance measures

Maintenance

Grouping of the measures

Inspection

Maintenance/Service

Repair

Targets of the measures = Definition in acc. with DIN 31051

Establishment and assessment of the actual

status

Preserving the required

status

Recovery of the required

status

Individual measures/activities

Test

Test

Repair

Measure

Adjust

Replace

Assess

Exchange

Amend

Lubricate

Preserve

Clean

The "Building services engineering maintenance working group of the VDMA (association of German
facility designer)" has issued data sheets, which act as a standard for the execution of maintenance
measures in the field of building services engineering. For all building services engineering areas, there are
data sheets for maintenance (see
Figure 3.G-35).

Figure 3.G-35 Composition of maintenance-related VDMA data sheets for building services engineering

VDMA data sheets

Status/
Valid

24
176

Inspection of air technology equipment and other technical equipment in buildings

1/90

24
186

Performance program for maintenance of air technology equipment and other

technical equipment in buildings

9/96

Part 0 Overview and structure, numbering system, general instructions

9/96

Part 1 Air technology systems

9/88

Part 2 Heating systems

9/88

Part 3 Cooling systems

9/88

Part
31

4/86

Electrically driven house heating pump systems for heating purposes

Part 4 Measuring and control technology equipment and building automation systems

9/88

Part 5 Electro-technical equipment and facilities

4/96

Part 6 Sanitary systems

5/92

24
196

Buildings management, terms and performances

8/96

24
243

Emissions reduction of cooling agents from cooling systems

Part 1 Introduction

5/94

Part 2 Construction and planning

5/94

Part 3 Assembly; Repair

5/94

Part 4 Maintenance; Repair; Disposal

5/94

Part 5 Specialist training, specialist plant equipment, operating instructions

5/94

Inspection is the subject of the VDMA 24176 "Inspection of air technology equipment and other technical
equipment in buildings" data sheet. Inspection includes testing and measuring activities, with the
evaluation and assessment of the results being an essential task, which should only be carried out by a
specially trained employee. Exact knowledge of the actual status is an important requirement for planning
maintenance measures.
Servicing includes the actual core task of planned maintenance. It includes all measures to ensure the
required status of the ventilation system and is the subject of the VDMA 24186 "Performance program for
servicing of air technology equipment and other technical equipment in buildings" data sheet. Details of
the various crafts of the technical building equipment are given in parts 0 to 6.
Based on the VDMA data sheets, it is possible to establish the measures to be executed for inspection and
servicing and their documentation. From the extensive collection of activities in these data sheets, the
corresponding performance pattern for the respective system can be compiled both for inspection and for
servicing.
The deadlines and intervals for inspection and servicing are to be established in a maintenance plan (see

Figure 3.G-38). Based on experience, the manufacturer's specifications and the significance of the facility,
periods must be defined in which an inspection or service is to be carried out (see
Figure 3.G-36).
To this end, the permissible tolerance periods within which the inspection or servicing must be carried out
should also be established (see
Figure 3.G-37).
Every maintenance measure must be documented. In general, for every activity on a ventilation system,
an entry should be made in the log book to be stored on-site or in the operating diary of the respective
system.
Documentation of the inspection or servicing activities that have been executed is carried out in the form
of records, which are filled in by the person executing the activity and counter-signed by a checker.
The following tables, records and diagrams show proven practical examples for the following maintenance
activities for air technology systems:

Time intervals for carrying out inspections or servicing (

Figure 3.G-36)

Tolerances for inspection and servicing deadlines (

Figure 3.G-37)

Maintenance plan (

Figure 3.G-38)

Forms: inspection of air technology equipment and systems (

Figure 3.G-39)

Forms: servicing of air technology equipment and systems (

Figure 3.G-40)

Form: log book for air technology systems (

Figure 3.G-42,

Figure 3.G-43,

Figure 3.G-44)

3.G.6.1 Time intervals for carrying out inspections or servicing

Figure 3.G-36 Time intervals for carrying out inspections or servicing
Frequency specifications relate to one year
Intervals

No servicing

1 x servicing

1 x servicing and

1 x servicing

Components

(only as required)
and 2 x inspections

and no
inspection

and 3 x
inspection

1 x inspection

Ventilation equipment for:

x

Offices

Non sterile
manufacturing

Laboratories

Clean rooms
(D, C, A + B)

Room control systems

Process air systems

Suspended matter filters

x
x

Laminar flow units

3.G.6.2 Tolerances for inspection and servicing deadlines

Figure 3.G-37 Tolerances for inspection and servicing deadlines
Deadlines for inspection and servicing

Tolerance

monthly

2 weeks

quarterly

1 month

half-yearly

2 months

yearly

3 months

3.G.6.3 Maintenance plan

Figure 3.G-38 Maintenance plan

to enlarge, click here!

3.G.6.4 Forms for the inspection and servicing of ventilation systems

The following examples of "Forms for the inspection and servicing of ventilation systems"are based on the
VDMA data sheets. The activities listed are a selection from the "Performance program for the servicing of
air technology equipment and other technical equipment in buildings" from VDMA data sheets 24186 part
1 and 4.
The design and handling of forms is intended as follows. The following entries are to be made in the
header of the forms:

the building

the storey

the facility name

the facility number

the component (if required)

The following columns are to be filled in as shown, in the rows with the individually described activities:
(the "available yes/no"column can be omitted if the forms only contain the components that are available
on the air technology systems).
Figure 3.G-39 Inspection of air technology equipment and systems in accordance with VDMA 24176

to enlarge, click here!

to enlarge, click here!

to enlarge, click here!

Figure 3.G-40 Servicing of air technology equipment and systems in accordance with VDMA 24176

to enlarge, click here!

to
enlarge,
click
here!

to
enlarge,
click

here!

to enlarge, click here!

to
enlarge,
click
here!

to
enlarge,
click

here!

3.G.6.5 Log book for air technology systems

The log book can be bound or can consist of individual sheets. A bound version has proven better in
practice, as this prevents the loss of individual sheets.
The example is structured as follows:
Figure 3.G-41 Figure 3.H-44 Completion of VDMA data sheets 24186 part 1 and 4
Column

Entry

"Available yes/no"

Cross the corresponding box

"Condition OK / not OK"

Cross the corresponding box

"Report or comment"

Findings, actual values, conditions that are not OK, executed activities,
servicing activities, etc. are to be described in words here.

A cover sheet (see

Figure 3.G-42)

"Inspection, servicing, repair, malfunction" form (page 1 to 20) (

Figure 3.G-43)

"Filter inspection, filter change" form (page 1 to 3) (see

Figure 3.G-44).

Figure 3.G-42 Example cover sheet

to enlarge, click here!

Figure 3.G-43 Example log book page

to enlarge, click here!

Figure 3.G-44 Example filter

to enlarge, click here!

Principles for entries in the log book

(See chapter 15.B GMP-conforming documentation.)

Entries in the log book are made on-site in chronological order (date and time) in the intended
forms, by the person executing the activity

The log book entry should be made during or immediately after completion of the activity. However,
under no circumstances should it be signed before completion of the activity in question.

After entry, any remaining blank fields are to be crossed out.

After completion of the activity by the person executing the work, the entries are confirmed through
the legible entry of a name and signature.

The entries in a log book page must be checked for completeness and accuracy and initialed by a
person in charge.

Entries should only be made with permanent ink pens.

The following entries must be made:

Date/time of activity

Type of activity, event (e.g. visual control, servicing, calibration, repair, malfunction)

Signature or signatures

An entry can be corrected by crossing it out. However, the old entry should still be legible after it
has been crossed out. It is not permissible to cover the entry or delete it with Tipp-Ex or Liquid
Paper. Correction or crossing out of an entry must then be confirmed by the person executing the
task by his signature and adding details of when it occurred.
Summary
The term "air technology" is split into the two terms "ventilation technology" and "process air
technology".
The ventilation system used is essentially determined by the following factors:

Influence of outside air

Climatic conditions of site

Operational costs of the different systems

Cleanliness requirements

Flexibility

In principle, it must be clarified if a recirculating air system is possible.

In order to guarantee the purity of the air in the premises of a pharmaceutical manufacturing site, suitable
filters must be used.
The design of a suitable ventilation system requires detailed recording of the planning principles and
specification of the GMP requirements in implementable designs.

The safe, fully functional and economic operation of a ventilation system requires a maintenance system.