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Business Management

Marketing

R&D GLP

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Engineering (GEP)

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GMP in the world

GMP by chapter: Pharmaceutical Quality System

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Documentation

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Quality Control

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3.H Heating Ventilation Air Conditioning (HVAC)Here you will find answers to the following questions:

What is understood by the term "air technology"?What kinds of air technology systems exist?What do air filters have to do?How are air technology systems maintained?What does qualification of air technology systems include?

3.H.1 Introduction

Pharmaceutical rules and specifications often contain very precise but also generally formulated requirements of air conditioningtechnology, such as "temperature, humidity and ventilation of premises should be adequate". This generally formulated requirement ispartially substantiated in the supplementary guideline of the EU GMP Guideline for the manufacture of sterile products, for example.

The following chapters give a practical description of the extensive, and sometimes complex field of air conditioning technology in terms ofthe 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 bythe terms room ventilation technology and process air conditioning technology. Both types are found and required in thepharmaceutical manufacturing sites. The essential task of a ventilation system is to guarantee the desired room conditions, such astemperature, humidity and cleanliness. In contrast, the process air systems must guarantee the required process parameters.

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

Figure 3.H-1 Structure of air conditioning technology

Separate Oil from WaterNo plates, filters or meshes. Low maintenance saves you money.

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Logistics GSP

GDP

IT (GAMP)

GPP

GACP

Terminology

Environmental management

Forum

References

About the project

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1. Belong to the equipment in the pharmaceutical manufacturing sites, e.g. fluid bed spray granulation, drying processes, coatingprocesses

2. Both types of ventilation systems "with" and "without" ventilation functions, as well as a combination of both are found in thepharmaceutical 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. Theterm ventilation function means that the air in the room is exchanged with external air. The further sub-structure shows the number ofthermodynamic air handling functions with which the ventilation system is equipped.

The thermodynamic air handling functions shown in figure 3.H-2 apply for the preparation of the inlet air: heating, cooling, humidifying anddehumidifying.

Figure 3.H-2 Classification of ventilation systems

Classification of room ventilation systemsVentilationfacilities

Recirculatingfacilities

Partial air conditioner

Recirculatingair partial airconditioners

Airconditioners

Recirculating airconditioners

Number of thermodynamic air handlingfunctions

None or one Two or three Four

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 engineering-related planning of ventilationsystems, but instead the focus is placed on the fundamental design, planning, solution options and implementation in terms of thepharmaceutical requirements.

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3.H.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.H-2 classification of ventilation systems).

The respective design and structure of the ventilation systems results from the requirements and conditions made of the ventilationsystem. (See chapter 3.H.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 airClimatic conditions of siteOperational costs of the different systems, especially the costs for energy consumption: current, heat, cold(cooling, dehumidification) and humidificationCleanliness requirementsFlexibility

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

3.H.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 thedefined conditions (temperature, humidity, purity). With a pure external air facility, impurities/contamination cannot enter the inlet airsystem via the exhaust air system. When using a heat recovery system, it must be ensured that the two systems cannot be connectedvia the heat recovery components (figure 3.H-3).

Figure 3.H-3 Diagram of a pure external air plant

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Pure external air conditioning system are used with the following conditions:

Supply of different production areas through a joint ventilation systemThe exhaust air from the rooms is so highly contaminated with impurities that no safe elimination ofimpurities is guaranteed 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 otherrequirements can be supplied without a risk of cross-contamination

3.H.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 befixed or can be variable according to the external temperature. Corresponding to the number of people working in the manufacturing site, aminimum external air share must not be undershot (figure 3.H-4).

Central recirculating air/mixed air conditioning system 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 safe elimination ofthe impurities is guaranteed 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 besupplied without a risk of cross-contamination.

Figure 3.H-4 Diagram of a central recirculating air/mixed air plant

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3.H.2.3 Decentralised 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 airguarantees the required external air share for the persons in the rooms (figure 3.H-5).

The recirculating air facility is usually fitted with a condenser and a filter stage.

Decentralised 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 systemThe concentration of impurities in the exhaust air from the rooms is so low that safe elimination of theimpurities is guaranteed via the cleaning/filter stages of the decentralised recirculating air facility.Flexibility, i.e. a manufacturing site for another product group with other requirement can be supplied atany time if the central external air preparation is carried out with a "pure external air plant".

Figure 3.H-5 Decentralised recirculating air/mixed air conditioning system with central external air preparation

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3.H.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 purerecirculating air facility is therefore only used for areas which are not permanently staffed and where the inlet of external air couldinfluence the air quality (figure 3.H-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 workbenches.

Figure 3.H-6 Pure recirculating air conditioning system

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3.H.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 post-heatingregisters or aftercoolers. The air currents (air volume) are today usually configured or regulated withvolume current regulators. With constant air currents, a very simple setting can be made via throttles suchas flaps and perforated plates (figure 3.H-7).Dual duct system: After the central air preparation facility, the inlet air is split across two differentlytempered air supply ducts. The air in the warm duct is heated to a temperature of 25 to 35 °C, while theair in the cold duct is cooled to 15 to 18 °C, for example. Before a room or zone, the two air flows aremixed in a blending box according to the required room temperature and heat burden, and blown in asinlet air. With the blending boxes, you can set constant air currents (air volume) or variable volumes(figure 3.H-8).

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

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

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3.H.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.H-9.

Figure 3.H-9 Comparison of volume current systems

Constant air volume flow Variable air volume flow

A fixed volume current is set via aconstant volume current regulator,blending box, flap or other throttle.

With a single duct facility, temperatureregulation takes place either by room orby zone via post-heating registers oraftercoolers.

Depending on the heat occurring in the room or in a zone and/or the activity, the air volumecurrents (inlet and exhaust air) can be raised from an initial value to a maximum value, e.g. viathe temperature regulation. With decreasing heat and/or activity, the air currents are reducedto the initial value again.

Advantages:

Simple design

Advantages:

Low energy consumption/costs

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Steadily working systems More flexible system, e.g. in terms of highly changeable heat burdensExternal influences can be ruled out, e.g. by pressure regulation due tochanging wind pressure.

Disadvantages:

High energyconsumption/costsCannot react to influences,or only marginally

Disadvantages:

More complex designHigher level of automation required

3.H.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 enablethermodynamic air handling functions such as heating, cooling, dehumidifying and humidifying. Energies that are used for heating, coolingand dehumidifying do not usually have any direct contact with the air to be prepared. The air is passed through heat exchangers which areequipped 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.H-10.

Figure 3.H-10 Energies and utilities for ventilation functions

Physical or thermodynamic functions Type of energy or utility

Air delivery Current

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

Cooling/dehumidifying Cooling water (e.g. 6/12 °C)Coolant

Humidifying WaterSteam

3.H.3 Filters

To realise the required air quality and conditions in the premises of a pharmaceutical manufacturing site, different standard componentsare 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. Thisrequires a suitable, correctly designed filter.

Air filters are components with which particles and gaseous impurities are filtered and separated from the air. The ambient air is penetratedby different substances of different particle sizes and different materials. This mixture of ingredients must be cleaned by suitable filters so

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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.H-11).

Figure 3.H-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 thereforeonly effective for very small particles. The molecular movement causes a diffuse movement of the particlealong a virtual streamline. It is separated at the fibre if it remains sufficiently close to the fibre for a longenough time.Inertness effect: The inertness effect causes separation at the fibres if the particle is of a particular sizeand 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 thefibre during circulation is less than half the particle diameter.

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

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

DIN EN 779 Particle air filter for general ventilationDIN EN 1822-1 Suspended matter filter (HEPA and ULPA) are the specifications and testing bases for allfilter manufacturers.:

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

3.H.3.1 Particle air filter

The particle air filters are classed in "coarse (C1 to C4)" and "fine (F5 to F 6)" filter groups in accordance with DIN EN 779 (see figure 3.H-13).

Figure 3.H-13 Classification of particle filters according to DIN EN 779

Initial effectiveness (EA) EA < 20% EA ³ 20%

Characteristics Average separation rate Am (%)Average effectiveness

Em (%)

Filter group Filter class Class limits

Coarse (C) g1

g2

g3

g4

Am < 65

5 Ј Am < 80

80 Ј Am < 90

80 Ј Am

-

-

-

-

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Fine (F) f5

f6

f7

f8

f9

-

-

-

-

-

40 Ј Em < 60

60 Ј Em < 80

80 Ј Em < 90

90 Ј Em < 95

95 Ј 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 therequired purity, total effectiveness of the filter > 95 %. This total effectiveness can only be achieved with fine filters in the 1st and 2ndfilter stage of air technology equipment.

The following combinations of filter classes are today used for two filter stages in series:

1st filter stage F 6 or F 72nd filter stage F 9

With this filter combination, the following targets are achieved:

Total effectiveness > 95%High period of use of the filterManageable energy costs

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

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 neighbouring plants), the dust content of the external airfluctuates.Velocity at which the air passes through the filter medium: With a reduced volume flow in relation tothe 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 rateincreases 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, asbacteria and fungus growth is encouraged near the dewpoint. The relative air humidity of the air flushingthrough should therefore not exceed a maximum value of 95 %.

The filter media used consist of fibreglass or synthetic-organic fibres, which are then connected thermally or chemically with bindingagents. The following models are generally used (see figure 3.H-14):

Filter mats ® Filter classes C1 to F 6Conveyor belt filter ® Filter classes G 1 to F 5Pocket filter ® Filter classes C1 to F 9

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

Figure 3.H-14 Models of air filters

Today, the separation rate or effectiveness of the particle air filters is determined as a percentage in comparison with "atmosphericdust" or "synthetic dust", without producing a reference to a particle size.

The first investigations and standardisation activities aim to determine a fractional separation rate for a defined particle size for thecomparison of the efficiency of a particle air filter.

Figure 3.H-15 Comparison of DIN EN 779 and Eurovent 4/9

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

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The diagram (see figure 3.H-16) shows a comparison of the separation rate (%) for the different particle sizes by pocket filters withdifferent filter classes. At present, the fractional separation rate should be calculated according to the Eurovent draft standard with aparticle size of 0.4 mm.

3.H.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 for in addition to the two particleair 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. justbefore 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 mm.

For the specification of the suspended matter filter, the different national standards were transferred into a European standard "DIN EN1822/T 1- 5" (see figure 3.H-17).

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

DIN EN 1822 Suspended matter filter (HEPA and ULPA)

Part Title Status/Valid

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1 Classification, performance test, labelling July 1998

2 Aerosol generation, measuring instruments, particle count statistic July 1998

3 Check of the planned filter medium July 1998

4 Leak test on the filter element (scan procedure) Open

5 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.H-18 with theassociated filtration performances.

Figure 3.H-18 Classification of HEPA and ULPA filtersaccording to their filtration performance in accordance with

DIN EN 1822 - 1)

Filter class

Integral value Local value

Separation rate (%)

Forward rate (%)

Separation rate (%)

Forward rate (%)

h10 85 15 - -

h11 95 5 - -

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 FilterULPA 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 theseparation rate minimum. The physical basis is the characteristic minimum curve which describes the separation behaviour of fibre filtersand thus also of suspended matter filters (see figure 3.H-19). The minimum lies in the transition area between stochastic movement(diffusion) through Brownian molecular movement and inertness effect as the determining separation mechanisms.

Figure 3.H-19 Characteristic minimum curve for describing the separation behaviour of fibre filters

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The position of the suspended matter filter's separation rate minimum, both in terms of the percentage separate rate and also of theparticle size with the highest penetration, depends on the velocity of the air flow through the filter medium. The particle size with thehighest penetration for a defined filter medium flow velocity is called the Most Penetration Particle Size (MPPS = separation rateminimum).

Through the connection between the filter medium flow velocity and separation performance, the separation performance of a suspendedmatter filter can be increased by reducing the medium velocity (see figure 3.H-20).

Figure 3.H-20 Two minimum curves of a suspended matter filter medium at different filter medium flow velocities

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The determination and assignment of the individual suspended matter filters to the filter classes is carried out in accordance with DIN EN1822. Here, the suspended matter filters of classes up to H 14 can be tested with the so-called oil strand test. As of filter class U15, aleak detection of the particle count method must be carried out, although the particle count method is already advisable even as of filterclass H 13.

Leakage test

With the oil strand test, a leak is visually detected, in that the filter element is acted upon by a high concentration paraffin cloud at theraw air side and a tester checks if identifiable oil strands are present at the pure air side. Every identified oil strand indicates the positionof a leak (figure 3.H-21).

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Figure 3.H-21 Schematic test structure for carrying out the leakage test on LF units

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

High precision of the measurementsDetermination of the total separation rate in the separation rate minimumDetermination of the local separation rateDetermination of leak positions

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

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Determination of the Minimum Penetration Particle Size (MPPS) with a defined filter medium flow velocityon a flat filter mediumFully scan the finished filter element with specified volume flow using MPPS particlesCalculation of the integral and local separation ratesClassification 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 testscannot usually be fully implemented when testing fitted suspended matter filters.

The test structure shown in figure 3.H-21 is possible when using the particle count method for fitted suspended matter filters:

The test aerosol is applied to 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 theinlet air duct.:

The particle concentration of at least 106/ft3 particles of 0.3 mm to be applied on the raw air side exceeds the count range of the particlecounter. 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 rawair 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 itspermissible 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 notachieved 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 inaccordance 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 aspossible on the limited designed space, the filter medium is folded (see figure 3.H-22 and figure 3.H-23).

The older type of fold is the separator technique. The filter medium is folded lengthways and widthways alternately and a separator ofcorrugated aluminium is inserted in the resulting chambers, which prevents the filter medium from coming into contact with itself and thuscreating an unusable filter surface. A disadvantage of the corrugated and sharp-edged aluminium separators is that they can tear the filtermedium 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 foldwith narrower spaces than the separator design. Thus, a greater filter surface can be realised in a suspended matter filter with a stranddesign of the same dimensions. The contact points of the spacers on the filter medium are significantly lower with the strand design thanwith 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 separatorsLower height with the same dimensions and filter surface

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Lower pressure losses.

Figure 3.H-22 Separator technique

Figure 3.H-23 Strand design

3.H.4 Principles for the design and planning of air conditioning ventilation systems

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When planning an air technology system, the principles must be clearly and unambiguously defined. For the ventilation systems to bedesigned and planned for a pharmaceutical manufacturing site, the external conditions of the site (see figure 3.H-24), the requirements ofthe premises (see figure 3.H-25), the production factors that influence the room climate (see figure 3.H-26) and the layout-dependentrequirements (see figure 3.H-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 summarised in a room log which must be available to every person involved in the planning. (See chapter 3.B.6 Roombook and layout.)

Figure 3.H-24 External conditions of the site

External conditions of the site

Externaltemperature

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 theneighbourhood)

Emissions ofharmful substances

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

Altitude Important, as the key fields of pumps and ventilators, for example, relate to the standardconditions.

Cardinal points Orientation of the building

Wind directions Main wind direction, wind speeds

Figure 3.H-25 Requirements of premises

Requirements of premises

Purity Cleanliness class of the rooms in accordance with the EU GMP Guideline, CFR (FDA), DIN ENISO 14644-1, VDI 2083.Special data on the required laminar ranges (cleanliness class A). Define size and position inthe layout.

Pressureconditions comparedwith borderingrooms/areas

Negative/positive pressure (e.g. 12.5 PA positive pressure between cleanliness classes)Alarm values, alert valuesWith defined pressure conditions, it must be defined how the pressure is built up/relieved overdifferent resistances (e.g. doors). Doors may have to be locked against each other.

Air flowdirection

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

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Temperature Temperature range (e.g. 19-25 °C), required temperature value (e.g. 22 °C), summercompensation, tolerance (e.g. ± 2 K), 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

Monitoringdevices

Particle concentrationsTemperaturesAir humidityPressure conditionsAir flow direction

Noise e.g. sound pressure level for production rooms 50-70 dB(A)

Figure 3.H-26 Usage-dependent requirements

Usage-dependent requirements

Manufacturing type Solid, liquid, sterile production, etc.

Hazard potentials of productionmaterials 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 processequipment

Required (inlet air and/or exhaust air) ® e.g. coating facilities,granulating facilities etc.

Sources of harmful substances that have to be recorded

DustSolventDisinfectant

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EX - protection requirements EX - zone classification of premises for production and engineering areasand for equipment

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

Sterilisation processesExternal heat loadsSimultaneity and durationof processes

Hot surfaces, emanating steam, etc.Through windows, walls, ceilingsImportant point to determine the "peak load"

Staff clothing Type of clothing that must be worn by the personnelParticularly important for temperature definitions if clean room clothing isworn.

Figure 3.H-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 mІ, length and width

Height of the rooms Room height in m

Definitions for thefacilitiesinfrastructure

Possibilities for the routing of supply and removal streetsDefinition of the philosophy in terms of the operation and maintenance of airtechnology components. (e.g. volume flow regulator, filter change from pure to impurearea)

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

Evaluation of the principles

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Using the formulated requirements and conditions, an air volume table can be compiled in relation to the rooms. The air volume table canbe used to summarise all important data for the air technology system. Figure 3.H-31 to figure 3.H-35 and figure 3.H-28 contain twoexamples 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

The second example shows the determination of the heat load in the room. This diagram is shown in Appendix 1 at the end of chapter 3(Figure 3.H-31 to figure 3.H-35).

Figure 3.H-28 Air volume table

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3.H.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 patternHow many filter stages are required and with what quality?® Air filter/stages/air filter qualityRoom conditions ® Temperature/humidity/summer compensationWhat air change is required? ® Air changeHow should the exhaust air be aspirated from the room? ® Exhaust air flow patternAre pressure differences or defined flows required between rooms or areas?® Room pressures/pressure stages/defined flowsHow are locks designed? ® Door locking/air flow pattern

Figure 3.H-29 lists the basic design features with solution approaches for the design of the room supply. The data does not relate to the

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design of air technology equipment.

Figure 3.H-29 Sterile room with negative pressure plenum

3.H.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.H-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 fanunits) are integrated in the ceiling between the sterile room and plenum. The filter fan units convey the air in the circuit between thesterile room and the plenum. The air is aspirated from the sterile room via aspiration points near the floor and conveyed to the plenum. Inaddition, the required fresh air is brought into the plenum as inlet air. The recirculating air and the inlet air are brought into the sterile roomas 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

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bordering areas, e.g. locks, engineering areas of autoclaves, etc. The overflow openings with constant air volumes are designed asgratings. 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 technicalsolutions for all listed components can be found.

3.H.5.2 Pressure stages and design of the pressure differential measurement for a sterile area

In accordance with the requirements, a pressure differential is realised between each cleanliness class. If each cleanliness area ismeasured at a reference point, this results in a clearly traceable record, e.g. with a line writer as the lines of the individual cleanlinessareas are always offset by the pressure differential. As the individual traces must be offset and parallel, it is easy to recognise if thecleanliness areas have always been in the prescribed pressure area.

The diagram (see figure 3.H-30) shows how the individual pressure differentials are always measured in relation to a reference point. Thealarms are determined from the differences between the cleanliness classes.

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

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For example, the following values could result from the individual pressure differential measurements:

PDIA 1: 12.5 Pa (pharmaceutical area/D area)PDIA 2: 25 Pa (pharmaceutical area/C area)PDIA 3: 32.5 Pa (pharmaceutical area/lock to sterile room)PDIA 4: 37.5 Pa (pharmaceutical area/sterile room)

Ventilation design criteria for GMP-conform production rooms

Figure 3.H-31 Calculation of cooling loads

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Figure 3.H-32 Ventilation and air-conditioning design - criteria for GMP-compliant production rooms (part 1)

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Figure 3.H-33 Ventilation and air-conditioning design - criteria for GMP-compliant production rooms (part 2)

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Figure 3.H-34 Ventilation and air-conditioning design - criteria for GMP-compliant production rooms (part 3)

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Figure 3.H-35 Ventilation and air-conditioning design - criteria for GMP-compliant production rooms (part 4)

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3.H.6 Maintenance of air ventilation systems

For pharmaceutical manufacturing sites, safe operation and functioning of the ventilation systems is an important requirement to be ableto guarantee the manufacture of pharmaceutical products in accordance with specific requirements and conditions for the premises.

The required activities and concepts in relation to the operation of a ventilation system can be shown based on DIN 32541 (see figure3.H-36).

Figure 3.H-36 Structure of the operation of a ventilation system based on DIN 32541

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For operation, maintenance is an essential factor for preserving safe, fully functional and economic operation in terms of the requiredstatuses (chapter 4.H Maintenance).

The following targets are pursued for air technology systems with planned and regularly executed maintenance measures (figure 3.H-37).

Figure 3.H-37 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

TestMeasureAssess

TestAdjustExchangeAmendLubricatePreserveClean

RepairReplace

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

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Guaranteeing a hygienic operation (purity, particle count etc.)Ensuring and increasing availabilityGuaranteeing economic operation (low energy costs)Identifying and eliminating weaknessesMaintaining the value of the system (longer life)

The "Building services engineering maintenance working group of the VDMA (association of German facility designer)" has issued datasheets which act as a standard for the execution of maintenance measures in the field of building services engineering. For all buildingservices engineering areas, there are data sheets for maintenance (see figure 3.H-38).

Figure 3.H-38 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 programme 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 Electrically driven house heating pump systems for heating purposes 4/86

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" datasheet. Inspection includes testing and measuring activities, with the evaluation and assessment of the results being an essential taskwhich should only be carried out by a specially trained employee. Exact knowledge of the actual status is an important requirement forplanning maintenance measures.

Servicing includes the actual core task of planned maintenance. It includes all measures to ensure the required status of the ventilationsystem and is the subject of the VDMA 24186 "Performance programme for servicing of air technology equipment and other technicalequipment 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 theirdocumentation. From the extensive collection of activities in these data sheets, the corresponding performance pattern for the respectivesystem 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.H-41). Based onexperience, the manufacturer's specifications and the significance of the facility, periods must be defined in which an inspection or service

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is to be carried out (see figure 3.H-39). To this end, the permissible tolerance periods within which the inspection or servicing must becarried out should also be established (see figure 3.H-40).

Every maintenance measure must be documented. In general, for every activity on a ventilation system, an entry should be made in thelog 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 filledin 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 technologysystems:

Time intervals for carrying out inspections or servicing (figure 3.H-39)Tolerances for inspection and servicing deadlines (figure 3.H-40)Maintenance plan (figure 3.H-41)Forms: Inspection of air technology equipment and systems (figure 3.H-42)Forms: Servicing of air technology equipment and systems (figure 3.H-43)Form: Log book for air technology systems (figure 3.H-45, figure 3.H-46, figure 3.H-47)

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

Figure 3.H-39 Time intervals for carrying out inspections or servicing

Frequency specifications relate to one year

Intervals No servicing (only as required)and 2 x inspections

1 x servicing and no inspection

1 x servicing and 1 x inspection1 x servicingand 3 x inspectionComponents

Ventilation equipment for:

Offices x

Non sterile manufacturing

x

Laboratories x

Clean rooms (D, C, A + B)

x

Room control systems x Process air systems x Suspended matter filters x Laminar flow units x

3.H.6.2 Tolerances for inspection and servicing deadlines

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Figure 3.H-40 Tolerances for inspection and servicingdeadlines

Deadlines for inspection and servicing Tolerance

monthly ± 2 weeks

quarterly ± 1 month

half-yearly ± 2 months

yearly ± 3 months

3.H.6.3 Maintenance plan

Figure 3.H-41 Maintenance plan

3.H.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. Theactivities listed are a selection from the "Performance programme for the servicing of air technology equipment and other technicalequipment in buildings" from VDMA data sheets 24186 part 1 and 4.

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The design and handling of forms is intended as follows. The following entries are to be made in the header of the forms:

the buildingthe storeythe facility namethe facility numberthe 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 canbe omitted if the forms only contain the components that are available on the air technology systems).

Figure 3.H-42 Inspection of air technology equipment and systems in accordance with VDMA 24176

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Figure 3.H-43 Servicing of air technology equipment and systems in accordance with VDMA 24176

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3.H.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 ofindividual sheets.

The example is structured as follows:

Figure 3.H-44 Completion of VDMA data sheets 24186 part 1 and 4

Column Entry

"Available yes/no" Cross the corresponding box

"Status" OK/notOK"

Cross the corresponding box

"Finding orcomment"

Here, findings, actual values, statuses that are not OK, executed activities, servicing activities, etc. are to bedescribed in words.

A cover sheet (see figure 3.H-45))"Inspection, servicing, repair, malfunction" form" (page 1 to 20) (see figure 3.H-46)"Filter inspection, filter exchange" form (page 1 to 3) (see figure 3.H-47).

Figure 3.H-45 Example cover sheet

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Figure 3.H-46 Example log book page

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Figure 3.H-47 Example filter

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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, bythe person executing the activityThe log book entry should be made during or immediately after completion of the activity. However, underno circumstances should it be signed before completion of the activity in question.After completion of the activity by the person executing the work, the entries are confirmed through thelegible entry of a name and signature.After entry, any remaining blank fields are to be crossed out.The entries in a log book page must be checked for completeness and accuracy and initialled by a personin charge.Entries should only be made with permanent ink pens.The following entries must be made:Date/time of activityType of activity, event (e.g. visual control, servicing, calibration, repair, malfunction)Signature or signaturesAn entry can be corrected by crossing it out. However, the old entry should still be legible after it has been

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crossed out. It is not permissible to cover the entry or delete it with Tipp-Ex. Correction or crossing out ofan entry must then be confirmed by the person executing the task, with the date and signature.

3.H.7 Qualification of air conditioning ventilation systems

Qualification of ventilation systems is incorporated in the overall concept of qualification for a manufacturing site. The overall qualificationconcept is described in a qualification master plan (see chapter 6.C.1 Qualification master plan). Thus, the qualification of ventilationsystems is part of the overall qualification of manufacturing sites. The aim of the qualification of a ventilation system is to prove that theventilation system is suitable for the manufacturing site in question.

The required scope of the qualification of ventilation systems depends on the extent to which compliance with the required parameterssuch as temperature, humidity, purity, pressure difference, etc. has a direct influence on the safe manufacturing of a pharmaceuticalproduct. Therefore, it is first necessary to estimate which parameters are relevant for the products.

Example: For a heat-sensitive product, the "room temperature" parameter is clearly product-relevant, if, for example, the stability of theproduct is no longer given at a product temperature of 23 °C or higher, and the product is open when processed, without the possibility ofdirect cooling. Thus, for the room in which the heat-sensitive product is processed, it must be proven that the ventilation system cancomply with the prescribed room temperature, e.g. 21 °C ± 1 K for all external conditions and that an alarm will be issued in the event ofdeviations.

On the other hand, there are many cases in which the room temperature does not have a direct influence on the product. It is thereforepossible to define the room temperature purely in accordance with the comfort criteria for production personnel, in accordance with therecommendations of DIN 1946/Part 2. (Example: room temperature 22 °C ± 2 K and summer compensation, i.e. the room temperature isgradually increased to 26 °C as of an external temperature of 26 °C to 32 °C.)

The following checklists (figure 3.H-48) give an overview of the most important checks that must be taken into account duringqualification of ventilation systems.

The following procedure has proven its worth in practice and has proven very viable:

Definition of the necessary qualification scope for the air technology system between production managersand qualification managersThe scope of qualification is documented in the checklists (figure 3.H-48 to figure 3.H-50) (fill in "Yes","No" and Comments columns). In accordance with the area to be supplied (e.g. sterile/non-sterile/specialproduct requirements), the qualification of the air technology system will include a greater or smallernumber of points.Signing of checklistsCompilation of detailed qualification plans based on the checklistsExecution of the individual qualification steps in accordance with the individual phases (IQ, OQ and PQ)Compilation of the respective reports

If qualification of the ventilation system is to be carried out by external employees or with external support, the completed checklists canbe used to request, offer and commission the scope of service to be provided externally by qualified providers.

Figure 3.H-48 Installation qualification checklist

Installation qualification (IQ) checklist required Comments

yes no

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1.1 System description and specifications

The aim is to document the requirements that must be met by the air technology system. If technicalmodifications that differ from the order are required by the manufacturer during production, these must also bedocumented. The following documents may be included in the system description or facility description:

a) Drawings such as R&I flow charts, installation diagrams, isometries, etc.

b) Requirements of the materials to be used

c) Performance data for the system, including system components

d) Definition of the type and quality of the utilities required for operation of the system, such as steam, water.

1.2 Documentation

The documentation is to be available at the latest two weeks before the first acceptance deadline.

The review of the documentation can extend over the entire period of the final acceptances and it is then to berevised in accordance with the correction notes.

The form and scope of the documentation provided should be in accordance with the guidelines/requirements of....in labelled DIN A4 folders.

The following documents can be included in the documentation:

System descriptionTabular air volume compositionDiagramsRI flow chartsFunction descriptionsEquipment card(s) of the air technology equipment, containing all components with therelevant data, e.g. electr. performance specifications, efficiencies, etc.

Equipment drawingsVentilators curvesLayout drawingsSectional drawingsDetailed drawingsCircuit diagramsSpare parts listsMaintenance instructions (inspection and servicing)Descriptions of individual components (e.g. air outlets, volume flow control device,shut-off flaps, etc.)Test certificates (e.g. TЬV, Ex, fire protection flaps, pressure checks, etc.)Measurement recordsAcceptance records

Calculations (e.g. pressure losses, noise values, air outlets, etc.)

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...

...

1.3 Installation checks

The installation qualification includes several testing steps which are not only limited to final acceptance.

The individual qualification checks are carried out throughout the entire construction phase. Final acceptancegroups together the individual checks.

1.3.1 Quality check at the contract acceptor or its suppliers

The contract giver reserves the right to check the following components of the contract acceptor's scope ofdelivery at the manufacturing site, at the construction site or in their final installation state.

The check will be carried out in accordance with the following conditions.

The following air technology equipment will be checked at the manufacturer:

............

............

............

............

1.3.1.2 The control tests at the manufacturer, with improvement specifications, can concern the following points:

ConstructionPerformanceCompliance with the requirements (e.g. materials)..Activity confirmation:

Air volumePressureEnergy consumption

Deficiencies and deviations are documented in a deficiencies list

1.3.1.3 Pressure testing of ventilation components (e.g. air conditioning device).

Air conditioning devices are subject to an endurance test.

The pressure testing is carried out under the following conditions:

Rated speed of the ventilator with closed air inlet covers or supports. (zero delivery).Proof of the static strength by falling below the permissible deflection of the externalwall by 0.5% of the air conditioning device height or width.

1.3.1.4 Other required test criteria can be agreed and added to this checklist.

1 ...

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2...

3 ...

1.3.2 Examination of the correct installation position of components

The contract acceptor is obligated to compile a checklist for all components in his scope of delivery (e.g. fireprotection flaps, volume flow regulators, blending boxes, flaps, air outlets, etc.), which permits easy and quickexamination on-site (e.g. using order lists).

The checklist should contain the test conditions and be compiled in the form of a table.

The following are checked

Manufacturer's installation instructionsFlow directionMaterials of componentsMake of componentsCorrect installation of componentsSafety devices availableAccessibility of componentsPurity status of the components...........

1.3.2.2 Duct tightness, permissible leak air flow for air conduction systems (DIN 24 194 Part 2)

The permissible leak air flow is based on the tightness class of the air conduction system

K I (no requirements)K II (higher requirements)K III (particularly high requirements)K IV (highest requirements)

with the assignment of the permissible leak air flow in

(m3/s)/m2 with a test pressure of

200 Pa,400 Pa,1000 Pa

The test pressure corresponds to the intended system pressure from the outgoing connections of the ventilationequipment. The permissible leak air flows are to be taken from DIN 24 194 Part 2.

Permissible leak air flow in (m3/s)/m2.

During assembly of the air conduction system, a section of the installed duct system is tested. If this test has anegative result, the entire duct network will be subject to a duct tightness test.

Constructions, operating procedures, assembly instructions are to be compiled in accordance with the valid GMPGuidelines and agreed/approved with the contract giver.

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E.g.:

Cleaning options for air systems (e.g. gradients, shut-off possibilities, review openings,etc.)Positioning of components (e.g. shut-off flap)Assembly instructions for pipe and duct systems: (especially important for clean areas)Clean pipes/ducts before assembly and seal with foils or sheet metal.Shortly before assembly, only the side to which the pipe/duct system is to beconnected may be opened.Open pipe and duct systems are to be sealed with foil each day after completion of thework................

1.3.3 Completeness test

The completeness test on the system is carried out on-site, when installed, using approved assembly drawings andorder lists supplemented with the test conditions.

Testing is carried out on the basis of the VDI Directive 2079

"Final acceptance testing of ventilation systems".

Test conditions:

1. Scope of delivery

2. Materials of components

3. Make of components

4. Correct installation of components

5. Safety devices available

6. Accessibility of components

7. Cleanliness status of the system

8. Inventory drawings

9. Operating instructions

10. Servicing instructions

11. Spare parts lists/spare parts

12. Test certificates/approval certificates (e.g. TЬV, Ex, fire protection flaps, pressure checks, etc.)

1.3.4 Calibration requirements

A list is compiled with the measuring and control instruments to be calibrated, including the acceptance criteria.

1.3.5 Log book

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The form and scope in which a log book should be compiled is established for the system.

1.3.6 Operating procedures

A decision is made on which operating procedures are required for the operation and servicing of the system.Existing operating procedures can be amended, used or new operating procedures can be compiled.

1............new/amend

2............new/amend

3............new/amend

1.3.7 Reports/servicing reports/malfunction reports

A list is compiled with all reports, showing if the report concerns operation, servicing or a malfunction.

Operator/date_________________________________________________

Quality assurance/date__________________________________________

Production (user)/date__________________________________________

Figure 3.H-49 Operational qualification checklist

Operational qualification (OQ) checklist required Comments

yes no The operational qualification includes the review of the individual components for operability, based on VDI 2079. Specifically, thefollowing are tests:

1. Ventilators 2. Filters 3. Heat exchangers 4. Humidification devices 5. Dehumidification devices 6. Heat recovery systems 7. Post-treatment equipment 8. Air ducts 9. Fire protection flaps 10. Air flaps 11. Filter seals 12. Volume flow regulators 13. Blending boxes, expansion boxes 14. Air openings 15. Measuring and control equipment 16. Calibrations of all sensors

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17. Test of the reports/alarm functions (incl. operation/servicing/malfunction)

18. Heat supply 19. Cold supply 20. Power supply 21. Steam supply 22. Condensate/water draining A list is created for each of the above-mentioned components, in which the tests to be carried out are establishedalong with the acceptance criteria to be complied with.

Operator/date_________________________________________________

Quality assurance/date__________________________________________

Production (user)/date__________________________________________

Figure 3.H-50 Performance qualification (PQ) checklist

Performance qualification (PQ) checklist required Comments

yes no Performance qualification means testing all given performance features, such as volume flow, pressure, humidity, temperature, airexchange counts, overflow devices, pressure differential values, air velocities, etc.

The performance qualification also includes testing of the individual measuring methods, execution of the measurements, the type ofdocumentation, in particular the description and calibration of the measuring instruments.

In addition to this, the test also includes the special requirements for testing clean rooms and their components, which are required toachieve the required particle count or classification.

Performance qualification is to be carried out by the contract acceptor and must be assigned the following contents.

3.1 Describe the aims of the PQ 3.2 Description of all measuring instruments used (e.g. measuring principle, measuring range, tolerances, etc.) 3.3 Testing of areas with and without defined particle count and ranges

In general, a PQ is carried out for each piece of equipment, each facility and each room. In each case, therequired values and actual values for the respective test requirements are to be listed in the form of tables withclear assignment.

3.3.1 Testing of areas without a defined particle count

The PQ is carried out on the basis of VDI 2079 and includes the following verifications:

3.3.1.1 Equipment testing

1. Power consumption and performance determinations of the drive motor

2. Pressure drop per item of equipment

3. Air supply temperature

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4. Inlet air humidity

5. Response limit of safety equipment

6. Safety switches

7. Register performance:Pressure losses in the register on the air side, temperatures before and after registers on the air side and on thewater side

8. Noise level in air current and outside the equipment

9. Efficiency of the heat recovery, proof of performance for heat recovery

10. Blending rate for recirculating air mixing, blending ratio and heat distribution after recirculating air mixing(operational proof of blenders).

11. Volume flow

12. Filter pressure difference

3.3.1.2 System testing

1. Air temperature in the storey distribution channel or at the end of the main distribution channel

2. Air humidity in the storey distribution channel or at the end of the main distribution channel

3. Air currents and velocities in the main channels and storey connections

4. Pressure drop in the main channels and storey distribution channels

5. Response limits of safety devices and safety sequenced actuation

6. Register performance, register pressure losses on air and water side for central post-treatment zones

3.3.1.3 Room testing

1. Air supply temperature at air outlet

2. Exhaust air temperature at room exit

3. Inlet and exhaust air volume flow with calculated proof of ambient air exchange (supply air)

4. Room temperature

5. Room air velocity

6. Room air humidity

7. Noise level

8. Overflow equipment in all openings

9. Room positive pressure to bordering rooms (D P)

10. Calculated proof of minimum external air rates

3.3.2 Additional tests for areas with a defined particle count

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3.3.2.1 Testing the air exchange of clean areas (class B, C, D)

Measurement of the volume flow of the suspended matter filter air outlets,documentation per filter (filter size, pressure loss, volume flow)Calculated proof of the room air exchange (inlet air), documentation per room (tabularlist)Calculated proof of the minimum external air supply, documentation per room

3.3.2.2 Testing the air velocity with low-turbulence laminar flow in accordance with operating procedure XXX

If there is no operating procedure, the execution of the measurement must be described in detail.

3.3.2.3 Proof of pressure zones

Room positive pressure/negative pressure to bordering rooms (D P)Air flow directions to bordering rooms, or in openings

3.3.2.4 Testing suspended matter filters

Visual inspectionTightness testing,scanning for leaks (with test aerosols)Leak test in accordance with VDI Directive 2083, sheet 3, point 5: Final acceptancemeasurements (Aerosol application possibility provided for at raw air side).Pressure loss

With duct suspended matter filters and suspended matter filters on the aspiration side, e.g. for process exhaustair, a suitable construction must be selected to enable these tests (e.g. install a special test ventilator)

3.3.2.5 Proof of the cleanliness classes in accordance with DIN EN ISO 14644-1

Operating statuses (see point. 2.4; DIN EN ISO 14644-1)Provision (see point. 2.4; DIN EN ISO 14644-1)Idle running (see point. 2.4; DIN EN ISO 14644-1)Manufacturing (see point. 2.4; DIN EN ISO 14644-1)Detailed description of the conditions:Operating statusesProduction machines (installed/ on/off)Personnel (production/technicians in measurement technology)Establishment of the sampling location

3.3.2.6 Flow pattern for class A/B and C

Proof of whether or not the flow pattern or room flushing meets the requirements.Under LF (class A)Laminarity of the initial air currentUnhindered flow against product contact parts

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Outside LF (class B and C)Prove turbulence of the flowsProof that air flows through all areas of the room (no dead corners, flow is turbulent).

The proof is to be documented visually with a video film, photos and an extensive report.

3.3.2.7 Recovery time

Testing of the recovery time of the clean room (e.g. class A/B) for:

Downtime of the facilities (determine the max. downtime)Impacts when doors are opened against black areas (escape doors)Targeted particle generation at critical points

Operator/date_________________________________________________

Quality assurance/date__________________________________________

Production (user)/date__________________________________________

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 airClimatic conditions of siteOperational costs of the different systemsCleanliness requirementsFlexibility

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 requirementsin implementable designs.

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

A prerequisite for the use of a ventilation system in a pharmaceutical manufacturing site is that the systems can be qualified.

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