Hvac Gmp Manual

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

1

Title

Classification, performance test, labeling

Status/Valid

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.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

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 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 μm 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 m² 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

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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

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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

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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

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

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

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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

x

x 

Laboratories



Clean rooms (D, C, A + B)

x

Room control systems

x

Process air systems Suspended matter filters

x x

Laminar flow units

x

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

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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

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

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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

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Figure 3.G-43 Example log book page

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 Figure 3.G-44 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, 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.