1. Part 3: Design, qualification
Supplementary Training Modules on GMP
Air Handling Systems
Heating
Ventilation and
Air Conditioning (HVAC)
Part 3: Design, qualification
and maintenance
In the first and second parts of this module, we have seen what the purpose of cleanroom classes are and how the air handling systems constitute the main factor in reaching the requirements of the cleanroom classes.
We have also seen what the different elements of air handling systems are, as well as some risks associated with them.
What we now want to study is how these elements are put together, how the systems are designed, and what must be done to ensure that they operate, and continue to operate, correctly.
The suggested time for Part 3 is minutes. At the conclusion of this part there is an optional group session ( minutes) and a test paper
(45 minutes).
(Note for the Trainer: the times noted are very approximate.)
Module 3, Part 3: Qualification and maintenance Slide 1 of 27
WHO - EDM

2. Characteristics of air handling systems
In the following slides, we will study alternatives in air handling systems
Turbulent or uni-directional airflows
Filter position
Air re-circulation vs fresh air
Return air systems (positions)
Overpressure requirements
There are many ways to design an air handling system, and we shall be examining the main alternatives, their advantages and disadvantages.
There are no “absolute” answers, and each factory has different requirements.
Turbulent or uni-directional airflows
Positioning of filters: filters in terminal position or not
Air re-circulation versus fresh air
Air return systems at low level or at ceiling level
Requirements for overpressure have been discussed in a previous part.

3. Uni-directional / laminar displacement of dirty air
Air flow patterns (1)
Turbulent
dilution of dirty air
Uni-directional / laminar
displacement of dirty air
0,30 m/s
There are 2 ways to supply air to a room or a piece of equipment:
• Turbulent air flow
Uni-directional flow, often called laminar flow
The air speed in the uni-directional flow is defined by the WHO at:
0,45 m/s for horizontal units
0,30 m/s for vertical units (most commonly used)
It is important to know that the WHO definition(*) for the air speed differs from those of other guidelines.
For the air exhaust, in case of a vertical unit, a low return is more favourable, as the air is better distributed in the room.
Objects in the room can significantly disturb the flow of air, and even block it, so that there might be pockets without air circulation.
During the qualification phase, the air flow is visualized if possible, and air samples are taken in different points, to make sure that there are no such pockets, in which case adjustments to the layout or to the air handling systems must be made.
(*) WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-second Report. Geneva, World Health Organization, 1992: (Technical Report Series, No. 823). Annex 1, 17.3.
Annex 1, 17.3

4. Air flow patterns (2)
Filtered air entering a production room or covering a process can be
turbulent
uni-directional (laminar)
GMP aspect
economical aspect
New technologies: barrier technology/isolator technology.
As seen in the previous slide, filtered air entering a production room or covering a process can be
Turbulent
Uni-directional (laminar)
Two aspects have to be considered:
GMP aspect: uni-directional air (laminar) installations give a better protection, because of the displacement effect rather than the dilution effect.
Economical aspect: turbulent air installations are cheaper, as less air has to be treated.
For certain operations, namely in class A, a “laminar flow” must be used.
It should be said here that such installations can give a false impression of security, and that the purpose of such installations is that there should be, whenever possible, no human interventions under them during the process. If interventions have to occur, they should be performed in a well-documented way, and recorded and evaluated for possible damage to the products.
The use of barrier technology systems (isolator technology) is highly recommended in cases of operations in class A, or for sterility testing operations.
Annex 1, 17.3, 17.4

5. AHU Air flow patterns (3) Uni-directional Turbulent Prefilter
Main filter
Uni-directional
Turbulent 1 2 3
Annex 1, 17.3
This slide shows an HVAC installation feeding 3 rooms, each one with terminal filters, all terminal filters protected by a remote pre-filter.
Room 1 has a turbulent air flow, with low level exhaust.
Room 2 has a uni-directional air flow, over the largest part of the surface, hence the large number of filters, with low level air returns.
Due to the high cost of the ventilation in class A areas, the tendency is to keep these areas as small as possible.
Room 3 has a turbulent air flow, with ceiling exhaust.
Good design practices recommend that cleanrooms A, B and C (ISO Class 5, 6 & 7) should have low level air returns.

6. Air flow patterns (4) Workbench (vertical) Cabin/ booth Ceiling
Uni-directional (laminar) flow units exist mostly as vertical, but also as horizontal, units.
Often, we are just dealing with LF workbenches (mainly used in sterility testing) or LF cabins/booths, routinely used in production, for instance on top of a filling machine.
In some cases, the units can be integrated into the ceiling of a room and also connected to the central air conditioning system.
Due to the high air velocity, it is important to have objects with good aerodynamical properties under the laminar flow. If not, turbulences and, therefore, particles are unavoidable.
Laminar flow units are comparatively expensive. Surfaces covered by them should be reduced to a minimum.
Only the product in a critical production phase, and not the personnel, should be under laminar flow (aseptic filling, sterile blending, etc.). Manual interventions should be restricted to a minimum, and should be recorded and evaluated for possible consequences.

7. Positioning of filters (1)
AHU mounted final filter
Filter in terminal position
HEPA Filter +
Production Room
Production Room
In some of the previous slides, we have seen filters both in the central air handling units ( AHU ) and terminally mounted at the production rooms.
The filtered air entering a production room can be coming from:
an air-handling unit, equipped with pre-filtration and the main (HEPA) filter, but at some distance from that room (left drawing);
an air-handling unit, equipped with pre-filtration in the AHU, and an additional filter (HEPA) situated immediately on the air outlet (right drawing).
In many cases, there are only filters in the AHU. However, for injectables and sterile forms, it is recommended that they be placed in terminal position, though there is a growing tendency to have terminal filters in all rooms where open products are handled. It is recommended that classes A & B (ISO 4, 5 & 6) have terminal HEPA filters. (Refer to: WHO Export Committee on Specifications for Pharmaceutical Preparations. Thirty-second Report. Geneva, World Health Organization, 1992:59-60 (Technical Report Series, No. 823). Annex 1, 17.3.)
If we look at the advantages and disadvantages of terminal or non-terminal filters, we can say that generally speaking, the terminal positioning
is more expensive;
provides a better protection (any problem arising from the ducts is eliminated);
is the preferred method in cleanroom classes with high requirements.
HEPA Filter

8. Positioning of filters (2)
Prefilter
AHU
Main filter
Ceiling
exhausts 2 3
Filters can be in different positions, when one considers the central AHU and the rooms.
This slide shows an HVAC installation feeding 3 rooms, each one with terminal filters, all filters protected by a remote pre-filter.
Room 1 has a turbulent air flow, with low level exhaust.
Room 2 has a uni-directional (laminar) air flow over the largest part of the surface, hence the large number of filters.
Room 3 has a turbulent air flow, with ceiling exhaust. 1
Low level exhausts

9. Positioning of filters (3)
AHU
Prefilter
Final filter 2 1
Positioning of filters (3)
This slide shows an HVAC installation feeding two rooms, each one without terminal filters, but with remote final filters protected by a pre-filter.
Room 1 has a turbulentair flow, with low level exhaust.
Room 2 has a turbulent air flow, with ceiling exhaust.
If there is no filter in terminal position, it should be ascertained that there are no elements between the main filter and the air outlets which could add contamination. No elements such as fans, heating/cooling batteries, should be situated downstream of the final filter.

10. Air re-circulation The filtered air entering a production room can be
100% exhausted or
a proportion re-circulated
GMP aspect
economical reasons
The filtered air entering a production room can be
eliminated at 100% (exhaust air)
a proportion re-circulated
Re-circulated air must be filtered, at an efficiency rate which is such that cross-contamination can be excluded.
In case of re-circulation, every possible measure of protection must be taken to ensure that the air coming from a production unit and loaded with product particles does not flow to other production units, thereby contaminating them.
It makes sense to re-circulate the air for reasons of energy conservation, but there can be a contradiction between pharmaceutical requirements and energy conservation.
There are also cases, in which air re-circulation is prohibited, for example if solvents are used or cytotoxic products are manufactured.
Annex 1, 15.10, 17.24

11. Ventilation with 100% fresh air (no air re-circulation)
Washer (optional)
Exhaust Unit W
This slide illustrates a typical 100% fresh air setup, where a central unit distributes the fresh, treated air to different production rooms.
The exhaust air is collected in a central duct, treated (filtered or washed) and eliminated. The degree of exhaust air filtration will depend on contaminants in the exhaust air and also on environmental regulations.
Central Air Handling Unit
Production Rooms
Annex 1, 17.24

12. Ventilation with re-circulated air + make-up air
Exhaust Unit
This slide illustrates a typical re-circulated air setup, where a central unit distributes a mixture of fresh and re-circulated air to different production rooms.
A part of the exhaust air is collected in a central duct, treated (filtered) and exhausted. The rest is re-circulated (dotted line).
With control dampers, the proportions of fresh and re-circulated air can be adjusted.
Central Air Handling Unit
Return air

13. Definition of Conditions
air
as built
at rest
in operation
When defining the requirements for a ventilation system for a room, and when testing it for the specified parameters, it is important to know what exactly has been requested from and specified by the suppliers, as values for particles and micro-organisms may differ largely between the conditions as built, at rest and in operation. Furniture/equipment can have an influence on the air flow and thus the air flushing, and people may influence the quantities of micro-organisms and particles.
Though WHO does not specify different values for both at rest and in operation situations, the need for accurate specifications for planning and operation still exists.

14. Qualification / Validation issues
A good design is essential, but it has to be complemented by:
Qualification of air handling systems
Process validation
Maintenance and periodic re-qualification
Adequate documentation
We have now seen why air handling plants are necessary, what their components are and what the alternatives are in their design.
However, we also have to remember that, once a ventilation system is installed, it is necessary to see how well it performs in comparison to its planned purpose, which is to provide a quality environment of specified parameters for the product.
We are now going to see how it is possible to
achieve
demonstrate
document
the required purity in practice by:
systems qualification and
process validation (media fill, for instance)
Additionally, good maintenance is essential.
The whole process is of course supported by adequate documentation.

15. Qualification (OQ, PQ) (1)
Test
Differential pressure on filters
Turbulent / mixed airflow
Description
Uni-directional airflow / LAF
Room differential pressure
Airflow velocity / uniformity
Airflow volume / rate
Parallelism
Air flow pattern 2
N/A
2, 3
Optional 3
1 := As built (ideally used to perform IQ)
2 = At rest (ideally used to perform OQ)
3 = Operational (ideally used to perform PQ)
IQ tests are not mentioned on this slide
Annex 1, 17. 4
This slide shows a series of tests to be carried out during qualification.
There are different tests for the turbulent and for the uni-directional air flows.
The differential pressure on filters is an indication of the clogging of the filters: with the charging of dust on the filters, the differential pressure will increase.
In order to keep the volume of air constant, the fan speed may increase, with the following consequences:
Damage to filters, and passage of unfiltered air
Particles and micro-organismes will be “pushed” through the filter units.
(Inspectors should check whether pressure differential manometers are installed on the AHUs. Without this means of monitoring the filters, the system could go out of control causing contamination problems.)
Airflow patterns are interesting to visualize (smoke tests), as zones without proper flushing can be easily identified.
It is also important to monitor air flow velocities for each HEPA filter according to a program of established intervals because significant reductions in velocity can increase the possibility of contamination, and changes in velocity can affect the laminarity of the airflow.
Airflow patterns should be tested for turbulence, as these can interfere with the flushing action of the air.

16. Qualification (OQ, PQ) (2)
Test
Turbulent / mixed airflow
Description
Uni-directional airflow / LAF
Recovery time
Room classification (airborne particle)
Temperature, humidity
N/A 2
2,3
1 := As built (ideally used to perform IQ)
2 = At rest (ideally used to perform OQ)
3 = Operational (ideally used to perform PQ)
Annex 1, 17. 4
The recovery time (clean-up time) is also an important parameter to be determined. Once doors have been opened and people have been entering a room, the original conditions have been disturbed and, for a short while, before recovering, the room does not always correspond to the laid down parameters. It is important to know how long this period is. There are no regulations laid down as to how long this clean-up time should be. However, the generally accepted time to clean-up from one cleanroom classification to the next higher classification, should be less than 15 minutes.
It should also be remembered that a room is to be qualified “in operation” when it has a certain number of people in it. After qualification, the number of people in that room, as challenged during qualification, cannot be exceeded.
Temperature and humidity can also be important (comfort in clean areas, stability of effervescent products, etc.)
IQ tests are not mentioned on this slide

17. Microbiological validation
Definition of alert / action limits as a function of
cleanliness zone
Identification and marking of sampling points
Definition of transport, storage, and incubation conditions
Ask the question: “What are the alert and action Limits and what procedures are followed if these points are exceeded?”
For the microbiological validation, it must be remembered that many factors may affect the results.
(Note to trainer: If required trainer should clarify diagram using white board.)
In order to have meaningful values, allowing corrective actions where necessary, there are a few basic points to be observed:
Clearly defined alert and action limits as a function of cleanliness zone (air sampling).
Clearly identified and marked sampling points, which should be correlated to production operations. The same sampling points or locations should be used for all future tests to ensure comparative results.
Procedures for sampling, transport, storage and incubation as the bacterial count may be influenced by these operations.
These elements have to be fixed and documented before starting the campaigns (as built, at rest, in operation).

18. Cleanroom monitoring program (1)
Cleanrooms should be monitored for micro-organisms
and particles
air
The environment should be monitored for particulate quality of the air in addition to microbiological quality. Critical areas should be monitored for particulates on at least a daily basis while the areas are in active use.
Air monitoring should be conducted adjacent to the filling location, surface monitoring product contact surfaces (filling needle assembly, stopper track, etc.) and non-contact surface adjacent to areas where product and open containers are present.
Periodic monitoring should be carried out to detect any significant changes in particle count from the normal level. Excessively higher numbers of particulates obtained from a given location would indicate something abnormal which should be investigated and promptly corrected.
Sampling point

19. Cleanroom monitoring program (2)
Routine monitoring program as part of quality assurance
Additional monitoring and triggers
Shutdown
Replacement of filter elements
Maintenance of air handling systems
Exceeding of established limits
A routine monitoring is of utmost importance and is part of the quality assurance program.
Maintenance and monitoring go hand in hand!
Therefore, after initial qualification and validation activities, a routine monitoring program should immediately be implemented.
The scope and approach of the routine monitoring program is simular to the activities listed before. This program must be documented and must include clearly defined roles and responsibilities.
In certain cases, additional monitoring can be necessary.
Triggers for additional monitoring could be:
Shutdown. In event of a power failure a time limit should be set based on qualification tests. In other words if the plant is off for longer than a pre-determined time period then the plant must be monitored and cleaned down as per SOP.
Replacement of filter elements
Maintenance of air handling systems
Exceeding of established limits (action limits)
Annex 1, 17.37

20. Cleanroom maintenance program (1)
WHO specifies that clean rooms should be monitored, as part of a regular maintenance program.
This slide shows an extract from the ISO standards, specifying tests to be performed within the frame of such a maintenance program.
These standards give some reference as to what to do and when, for the testing of the systems, after installation.
The tests to be performed depend on the ISO class considered.
Some of the tests, such as the particle count test, require specialized equipment; such services are frequently contracted to outside, specialists.

21. Cleanroom maintenance program (2)
Some tests are compulsory, some additional (optional).
The air flow visualization (smoke test) is performed using, for instance, steam as a visualization agent. It is a good practice to video-record such tests.
Here too, some of the tests, such as the leakage test, require particular equipment. Such services are frequently contracted to outside, specialized companies.
This slide concludes the design, qualification and maintenance issues.

22. Documentation requirements
Description of installation and functions
Specification of the requirements
Operating procedures
Instructions for performance control
Maintenance instructions and records
Maintenance records
Training of personnel (program and records)
The following slides illustrate the documentation requirements for the design, installation, qualification, operation and maintenance of an air handling plant.
This documentation, necessary for a good GMP operation of an air handling plant, consists of several elements:
Complete description of installation (drawings, installed elements, description of the elements, etc.).
Specification of the requirements: What is the system supposed to do? Which values is it supposed to reach?
Operating procedures: how to operate the system.
Performance control: how to judge if everything is operating perfectly (fan, filters, etc.).
How to maintain the system.
Maintenance records showing that the system has been properly maintained.
Personnel training, showing that human resources are at hand to properly operate and maintain the system.

23. Inspecting the air handling plant
Verification of design documentation, including
description of installation and functions
specification of the requirements
Operating procedures
Maintenance instructions
Maintenance records
Training logs
Environmental records
Discussion on actions if OOS values
Walking around the plant
This slide summarizes the main elements of an inspection and the various items to be checked:
How was the plant designed? Rationale for chosen solutions? Are they adequate? Has a good documentation system (instructions and records) been set up?
Are operating procedures available for inspection?
Are maintenance plans implemented?
Check the maintenance records.
Is environmental contamination being checked? Are records available?
Check that training has been carried out by checking the training logs.
Are the values in line with the specifications, and if not, what happens?
(OOS = Out of Specification values)
Finally, a walk through the HVAC plant (often difficult to access, and therefore neglected) will give a good picture on the GMP awareness of the engineering. Check for equipment labeling, flow direction arrows, pressure gauge max and min markings, etc.

24. Conclusion Air handling systems:
Play a major role in the quality of pharmaceuticals
Must be designed properly, by professionals
Must be treated as a critical system
In conclusion, it can be said that:
Air handling systems
Play a major role in the quality of Pharmaceuticals, as they will have a large impact on contamination and cross-contamination.
Must be designed properly, by professionals. Many designers of HVAC plants have no relevant pharmaceutical experience.
Must be treated as critical systems, in view of their importance, especially in sterile areas.

25. Further proceedings
This series of explanations will now be followed by:
Group discussion, with a simple exercise
Short test
This series of explanations will now be followed by:
Group discussion (optional) (45-60 minutes)
Short test (45 minutes)

26. Group Session
The diagram, which is given in handout , shows a layout of a small pharmaceutical plant for non-sterile tablets, liquids and soft-gel capsules, as well as aseptically filled eye-drops.
The group session participants should indicate on the diagram the required cleanroom classes, room pressures (in Pa), as well as any architectural changes which they think necessary.
(This layout is not ideal, but as many different types of operations have been incorporated in the facility as possible, so that different concepts can be addressed.)
(Note to trainer: The next handout, , giving suggested modifications, should not be distributed until after the group discussion has taken place.)

27. Group Session – modified layout
This slide indicates the proposed additions, and can be displayed after the group session discussions have taken place. See handout
MAL = Material Air Lock
PAL = Personnel Air Lock