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HVAC systems for non-sterile pharmaceutical as per WHO TRS. 937, 2006 ,Annex 2

WHO Technical Report Series, No. 937, 2006 ,Annex 2

Supplementary guidelines on good manufacturing practices for heating, ventilation and air-conditioning systems for
non-sterile pharmaceutical dosage forms

1. Introduction
2. Scope of document
3. Protection
3.1 Products and personnel
3.2 Air filtration
3.3 Unidirectional airflow
3.4 Infiltration
3.5 Cross-contamination
3.6 Temperature and relative humidity
4. Dust control
5. Protection of the environment
5.1 Dust in exhaust air
5.2 Fume removal
6. Systems and components
6.1 General
6.2 Recirculation system
6.3 Full fresh air systems
7. Commissioning, qualification, and maintenance
7.1 Commissioning
7.2 Qualification
7.3 Maintenance

8. Glossary

1. Introduction:

Heating, ventilation, and air-conditioning (HVAC) play an important role in ensuring the manufacture of quality pharmaceutical products. A well-designed HVAC system will also provide comfortable conditions for operators.

HVAC system design influences architectural layouts with regard to items such as airlock positions, doorways and lobbies. The architectural components have an effect on room pressure differential cascades and cross-contamination control. The prevention of contamination and cross-contamination is an essential design consideration of the HVAC system.

Temperature, relative humidity, and ventilation should be appropriate and should not adversely affect the quality of pharmaceutical products during their manufacture and storage, or the accurate functioning of equipment.

2.Scope of document:

These guidelines focus primarily on the design and good manufacturing practices (GMP) requirements for HVAC systems for facilities for the manufacture of solid dosage forms, most of the system design principles for facilities manufacturing solid dosage forms also apply to other facilities such as those manufacturing liquids, creams, and ointments.

The three primary roles of HVAC system plays in product protection, personnel protection, and environmental protection (Fig. 1).

Figure 1
The guidelines address the various system criteria according to the sequence set out in this diagram

 

3. Protection
3.1 Product and personnel

  • Areas for the manufacture of pharmaceuticals, where pharmaceutical starting materials and products, utensils, and equipment are exposed to the environment, should be classified as “clean areas”.
  • Some of the basic criteria to be considered should include:
  • Building finishes and structure
  • Air filtration
  • Air change rate or flushing rate
  • Room pressure
  • Location of air terminals and directional airflow
  • Temperature
  • Humidity
  • Material flow
  • Personnel flow
  • Equipment movement
  • Process being carried out
  • Outside air conditions
  • Occupancy
  • Type of product.
  • Air filtration and air change rates should ensure that the defined clean area classification is attained.
  • Air change rates normally vary between 6 and 20 air changes per hour and are normally determined by the following considerations:
  • Level of protection required
  • The quality and filtration of the supply air
  • Particulates generated by the manufacturing process
  • Particulates generated by the operators
  • Configuration of the room and air supply and extract locations
  • Sufficient air to achieve containment effect
  • Sufficient air to cope with the room heat load
  • Sufficient air to maintain the required room pressure.
  • In classifying the environment, the manufacturer should state whether this is achieved under “as-built” (Fig. 2), “at-rest” (Fig. 3), or “operational” (Fig. 4) conditions.

  • Room classification tests in the “as-built” condition should be carried out on the bare room, in the absence
    of any equipment or personnel.
  • Room classification tests in the “at-rest” condition should be carried out with the equipment operating where relevant, but without any operators. Because of the amounts of dust usually generated in a solid
    dosage facility most clean area classifications are rated for the “at-rest” condition
  • Room classification tests in the “operational” condition should be carried out during the normal production process with equipment operating, and the normal number of personnel present in the room. Generally, a room that is tested for an “operational” condition should be able to be cleaned up to the “at-rest” clean area classification after a short clean-up time. The clean-up time should be determined through validation and is generally of the order of 20 minutes.
  • Materials and products should be protected from contamination and cross-contamination during all stages of manufacture

Note: contaminants may result from inappropriate premises (e.g. poor design, layout, or finishing), poor cleaning procedures, contaminants brought in by personnel, and a poor HVAC system.

  • Airborne contaminants should be controlled through effective ventilation.
  • External contaminants should be removed by effective filtration of the supply air. (See Fig. 5 for an example of a shell-like building layout to enhance containment and protection from external contaminants.)
  • Internal contaminants should be controlled by dilution and flushing of contaminants in the room, or by displacement airflow.w (See Figs 6 and 7 for examples of methods for the flushing of airborne contaminants.)
  • Airborne particulates and the degree of filtration should be considered critical parameters with reference to the level of product protection required.

The level of protection and air cleanliness for different areas should be determined according to the product being manufactured, the process being used, and the product’s susceptibility to degradation (Table 1).

Air filtration
Note: The degree to which air is filtered plays an important role in the prevention of contamination and the control of cross-contamination.
4.2.1 The type of filters required for different applications depends on the quality of the ambient air and the return air (where applicable) and also on the air change rates. Table 2 gives the recommended filtration levels for
different levels of protection in a pharmaceutical facility. Manufacturers should determine and prove the appropriate use of filters.

Filter classes should always be linked to the standard test method because referring to actual filter efficiencies can be very misleading (as different test methods each result in a different value for the same filter) (Fig. 8).

In selecting filters, the manufacturer should have considered other factors, such as particularly contaminated ambient conditions, local regulations, and specific product requirements. Good prefiltration extends the
life of the more expensive filters downstream.

Materials for components of an HVAC system should be selected with care so that they do not become the source of contamination. Any component with the potential for liberating particulate or microbial contamination into the air stream should be located upstream of the final filters.

Ventilation dampers, filters, and other services should be designed and positioned so that they are accessible from outside the manufacturing areas (service voids or service corridors) for maintenance purposes.

Personnel should not be a source of contamination

Directional airflow within production or packing areas should assist in preventing contamination. Airflows should be planned in conjunction with operator locations, so as to minimize contamination of the product by the operator and also to protect the operator from dust inhalation.

HVAC air distribution components should be designed, installed, and located to prevent contaminants generated within the room from being spread.

Supply air diffusers of the high induction type (e.g. those typically used for office-type air-conditioning) should where possible not be used in clean areas where dust is liberated. Air diffusers should be of the non-induction type,
introducing air with the least amount of induction so as to maximize the flushing effect (see Figs 9–11 for illustrations of the three types of diffuser.)

Whenever possible, air should be exhausted from a low level in rooms to help provide a flushing effect.

 

Unidirectional airflow
Unidirectional airflow (UDAF) should be used where appropriate to provide product protection by supplying a clean
air supply over the product, minimizing the ingress of contaminants from surrounding areas.

Where appropriate, the unidirectional airflow should also provide protection to the operator from contamination by
the product.

Sampling of materials such as starting materials, primary packaging materials, and products should be carried out in
the same environmental conditions that are required for the further processing of the product

In a weighing booth situation, the aim of the design using UDAF should be to provide dust containment.

A dispensary or weighing booth should be provided with unidirectional airflow for protection of the product and operator.

The source of the dust and the position in which the operator normally stands should be determined before deciding on the direction of unidirectional flow.

Example: In Fig. 12 the dust generated at the weighing station is immediately extracted through the perforated worktop, thus protecting the operator from dust inhalation, but at the same time protecting the product from contamination by the operator by means of the vertical unidirectional airflow stream.

The unidirectional flow velocity should be such that it does not disrupt the sensitivity of balances in weighing areas. Where necessary the velocity may be reduced to prevent inaccuracies during weighing, provided that sufficient airflow is maintained to provide containment.

The position in which the operator stands relative to the source of dust liberation and airflow should be determined to ensure that the operator is not in the path of an airflow that could lead to contamination of the product (Fig. 13).

Once the system has been designed and qualified with a specific layout for operators and processes, this should be maintained in accordance with an SOP

There should be no obstructions in the path of a unidirectional flow air stream that may cause the operator to be exposed to dust.

Fig. 14 illustrates the incorrect use of a weighing scale which has a solid back. The back of the weighing scale should not block the return air path as this causes air to rise vertically, resulting in a hazardous situation for the operator

Fig. 15 illustrates a situation where an open bin is placed below a vertical unidirectional fl ow distributor. The downward airflow should be prevented from entering the bin, and then being forced to rise again, as this would
carry dust-up towards the operator’s face.

Fig. 16 shows that a solid worktop can sometimes cause deflection of the vertical unidirectional airflow resulting in a flow reversal. A possible solution would be to have a 100 mm gap between the back of the table and the
wall, with the air being extracted here.

The manufacturer should select either vertical or horizontal unidirectional flow (Fig. 17) and an appropriate airflow pattern to provide the best protection for the particular application.

Infiltration:

Air infiltration of unfiltered air into a pharmaceutical plant should not be the source of contamination.

Manufacturing facilities should be maintained at a positive pressure relative to the outside, to limit the ingress of contaminants. Where facilities are to be maintained at negative pressures relative to the ambient pressure
to prevent the escape of harmful products to the outside (such as penicillin and hormones), special precautions should be taken.

The location of the negative pressure facility should be carefully considered with reference to the areas surrounding it, particular attention being given to ensuring that the building structure is well sealed.

Negative pressure zones should, as far as possible, be encapsulated by surrounding areas with clean air supplies, so that only clean air can infiltrate into the controlled zone.

Cross-contamination

Where different products are manufactured at the same time, in different areas or cubicles, in a multiproduct OSD manufacturing site, measures should be taken to ensure that dust cannot move from one cubicle to another.

Correct directional air movement and a pressure cascade system can assist in preventing cross-contamination. The pressure cascade should be such that the direction of airfl ow is from the clean corridor into the cubicles,
resulting in dust containment.

The corridor should be maintained at a higher pressure than the cubicles, and the cubicles at a higher pressure than atmospheric pressure.

Containment can normally be achieved by application of the displacement concept (low-pressure differential, high airflow), or the pressure differential concept (high-pressure differential, low airflow), or the physical barrier concept.

The pressure cascade regime and the direction of airflow should be appropriate to the product and processing method used

Highly potent products should be manufactured under a pressure cascade regime that is negative relative to atmospheric pressure.

The pressure cascade for each facility should be individually assessed according to the product handled and level of protection required.

Building structure should be given special attention to accommodate the pressure cascade design.

Airtight ceilings and walls, close-fitting doors, and sealed light fittings should be in place.

Displacement concept (low-pressure differential, high airflow)

Note: This method of containment is not the preferred method, as the measurement and monitoring of airfl ow velocities in doorways is difficult. This concept should ideally be applied in production processes where large
amounts of dust are generated.

Under this concept, the air should be supplied to the corridor, flow through the doorway, and be extracted from the back of the cubicle. Normally the cubicle door should be closed and the air should enter the cubicle through a door grille, although the concept can be applied to an opening without a door.

The velocity should be high enough to prevent turbulence within the doorway resulting in dust escaping.

This displacement airflow should be calculated as the product of the door area and the velocity, which generally results in fairly large air quantities.

Pressure differential concept (high-pressure differential, low airflow)

Note: The pressure differential concept may normally be used in zones where little or no dust is being generated. It may be used alone or in combination with other containment control techniques and concepts, such as a
double door airlock

The high-pressure differential between the clean and less clean zones should be generated by leakage through the gaps of the closed doors to the cubicle.

The pressure differential should be of sufficient magnitude to ensure containment and prevention of flow reversal, but should not be so high as to create turbulence problems

In considering room pressure differentials, transient variations, such as machine extract systems, should be taken into consideration.

Note: The most widely accepted pressure differential for achieving containment between two adjacent zones is 15 Pa, but pressure differentials of between 5 Pa and 20 Pa may be acceptable. Where the design pressure differential is too low and tolerances are at opposite extremities, a flow reversal can take place. For example, where a control tolerance of ± 3 Pa is specified, the implications of the upper and lower tolerances on containment should be evaluated.

The pressure differential between adjacent rooms could be considered a critical parameter, depending on the outcome of risk analysis. The limits for the pressure differential between adjacent areas should be such that there
is no risk of overlap, e.g. 5 Pa to 15 Pa in one room and 15 Pa to 30 Pa in an adjacent room, resulting in no pressure cascade, if the first room is at the maximum tolerance and the second room is at the minimum tolerance.

Low-pressure differentials may be acceptable when airlocks (pressure sinks or pressure bubbles) are used

The effect of room pressure tolerances are illustrated in Fig. 18.

The pressure control and monitoring devices used should be calibrated and qualified. Compliance with specifications should be regularly verified and the results recorded. Pressure control devices should be linked to an
alarm system set according to the levels determined by a risk analysis,

Manual control systems, where used, should be set up during commissioning and should not change unless other system conditions change.

Airlocks can be important components in setting up and maintaining pressure cascade systems.

Airlocks with different pressure cascade regimes include the cascade airlock, sink airlock, and bubble airlock (Figs 19–21).
• Cascade airlock: high pressure on one side of the airlock and low pressure on the other.
• Sink airlock: low pressure inside the airlock and high pressure on both outer sides.
• Bubble airlock: high pressure inside the airlock and low pressure on both outer sides.

 

 

Doors should open to the high-pressure side, and be provided with self-closers. Door closer springs, if used, should be designed to hold the door closed and prevent the pressure differential from pushing the door open. Sliding doors are not recommended.

Central dust extraction systems should be interlocked with the appropriate air handling systems, to ensure that they operate simultaneously.

Room pressure imbalance between adjacent cubicles which are linked by common dust extraction ducting should be prevented.

Air should not flow from the room with the higher pressure to the room with the lower pressure, via the dust extract ducting (this would normally occur only if the dust extraction system was inoperative).

Physical barrier concept:

 

Temperature and relative humidity

Temperature and relative humidity should be controlled, monitored and recorded, where relevant, to ensure compliance with requirements pertinent to the materials and products, and to provide a comfortable environment for the operator where necessary.

Maximum and minimum room temperatures and relative humidity should be appropriate.

Temperature conditions should be adjusted to suit the needs of the operators while wearing their protective clothing.

The operating band, or tolerance, between the acceptable minimum and maximum temperatures should not be made too close.

Cubicles, or suites, in which products requiring low humidity are processed, should have well-sealed walls and ceilings and should also be separated from adjacent areas with higher humidity by means of suitable airlocks.

Precautions should be taken to prevent moisture migration that increases the load on the HVAC system.

Humidity control should be achieved by removing moisture from the air, or adding moisture to the air, as relevant.

Dehumidification (moisture removal) may be achieved by means of either refrigerated dehumidifiers or chemical dehumidifiers.

Appropriate cooling media for dehumidification such as low-temperature chilled water/glycol mixture or refrigerant should be used.

Humidifiers should be avoided if possible as they may become a source of contamination (e.g. microbiological growth). Where humidification is required, this should be achieved by appropriate means such as the injection of steam into the air stream. A product-contamination assessment should be done to determine whether pure or clean steam is required for the purposes of humidification.

Where steam humidifiers are used, chemicals such as corrosion inhibitors or chelating agents, which could have a detrimental effect on the product, should not be added to the boiler system.

Humidification systems should be well-drained. No condensate should accumulate in air-handling systems.

Other humidification appliances such as evaporative systems, atomizers, and water mist sprays, should not be used because of the potential risk of microbial contamination.

Duct material in the vicinity of the humidifier should not add contaminants to air that will not be filtered downstream.

Air filters should not be installed immediately downstream of humidifiers.

Cold surfaces should be insulated to prevent condensation within the clean area or on air-handling components.

When specifying relative humidity, the associated temperature should also be specified.

Chemical driers using silica gel or lithium chloride are acceptable, provided that they do not become sources of contamination.

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8.Glossary:

Acceptance criteria
Measurable terms under which a test result will be considered acceptable.
Action limit
The action limit is reached when the acceptance criteria of a critical parameter have been exceeded. Results outside these limits will require specified action and investigation.
Air-handling unit (AHU)
The air-handling unit serves to condition the air and provide the required air movement within a facility.
Airlock
An enclosed space with two or more doors, which is interposed between two or more rooms, e.g. of differing classes of cleanliness, for the purpose of controlling the airflow between those rooms when they need to be entered. An airlock is designed for and used by either people or goods (PAL, personnel airlock; MAL, material airlock).
Alert limit
The alert limit is reached when the normal operating range of a critical parameter has been exceeded, indicating that corrective measures may need to be taken to prevent the action limit being reached.
As-built
A condition where the installation is complete with all services connected and functioning but with no production equipment, materials, or personnel present.
At-rest
A condition where the installation is complete with equipment installed and operating in a manner agreed upon by the customer and supplier, but with no personnel present.
Change control
A formal system by which qualified representatives of appropriate disciplines review proposed or actual changes that might affect a validated status. The intent is to determine the need for action that would ensure that the system is maintained in a validated state.

clean area (clean room) 
An area (or room) with defined environmental control of particulate and microbial contamination, constructed and used in such a way as to reduce the introduction, generation, and retention of contaminants within the area.
Commissioning
Commissioning is the documented process of verifying that the equipment and systems are installed according to specifications, placing the equipment into active service, and verifying its proper action. Commissioning takes
place at the conclusion of project construction but prior to validation.
Containment
A process or device to contain product, dust, or contaminants in one zone, preventing it from escaping to another zone.
Contamination
The undesired introduction of impurities of a chemical or microbial nature, or of foreign matter, into or on to a starting material or intermediate, during production, sampling, packaging, or repackaging, storage, or transport.
Critical parameter or component
A processing parameter (such as temperature or humidity) that affects the quality of a product, or a component that may have a direct impact on the quality of the product.
Cross-contamination
Contamination of a starting material, intermediate product, or finished product with another starting material or material during production.
Design condition
Design condition relates to the specified range or accuracy of a controlled variable used by the designer as a basis for determining the performance requirements of an engineered system.
design qualification (DQ)
DQ is the documented check of planning documents and technical specifications for conformity of the design with the process, manufacturing, GMP, and regulatory requirements.

Direct impact system
A system that is expected to have a direct impact on product quality. These systems are designed and commissioned in line with good engineering practice (GEP) and, in addition, are subject to qualification practices.
Facility
The built environment within which the clean area installation and associated controlled environments operate together with their supporting infrastructure.
Good engineering practice (GEP)
Established engineering methods and standards that are applied throughout the project life-cycle to deliver appropriate, cost-effective solutions.
Indirect impact system
This is a system that is not expected to have a direct impact on product quality but typically will support a direct impact system. These systems are designed and commissioned according to GEP only.
Infiltration
Infiltration is the ingress of contaminated air from an external zone into a clean area.
Installation qualifi cation (IQ)
IQ is documented verification that the premises, HVAC system, supporting utilities, and equipment have been built and installed in compliance with their approved design specification.
No-impact system
This is a system that will not have any impact, either directly or indirectly, on product quality. These systems are designed and commissioned according to GEP only.
Non-critical parameter or component
A processing parameter or component within a system where the operation, contact, data control, alarm, or failure will have an indirect impact or no impact on the quality of the product.
Normal operating range
The range that the manufacturer selects as the acceptable values for a parameter during normal operations. This range must be within the operating range.
Operating limits
The minimum and/or maximum values that will ensure that product and safety requirements are met.

Operating range
Operating range is the range of validated critical parameters within which acceptable products can be manufactured.
Operational condition
This condition relates to carrying out room classification tests with the normal production process with equipment in operation, and the normal staff present in the room.
operational qualification (OQ)
OQ is the documentary evidence to verify that the equipment operates in accordance with its design specifications in its normal operating range and performs as intended throughout all anticipated operating ranges.
Oral solid dosage (OSD)
Usually refers to an OSD plant that manufactures medicinal products such as tablets, capsules, and powders to be taken orally.
Performance qualification (PQ)
PQ is the documented verification that the process and/or the total process related to the system performs as intended throughout all anticipated operating ranges.
Point extraction
Air extraction to remove dust with the extraction point located as close as possible to the source of the dust.
Pressure cascade
A process whereby air flows from one area, which is maintained at a higher pressure, to another area at a lower pressure.
Qualification
Qualification is the planning, carrying out and recording of tests on equipment and a system, which forms part of the validated process, to demonstrate that it will perform as intended.
Relative humidity
The ratio of the actual water vapour pressure of the air to the saturated water vapour pressure of the air at the same temperature expressed as a percentage. More simply put, it is the ratio of the mass of moisture in the air, relative to the mass at 100% moisture saturation, at a given temperature.
Standard operating procedure (SOP)
An authorized written procedure, giving instructions for performing operations, not necessarily specific to a given product or material, but of a more general nature (e.g. operation of equipment, maintenance, and cleaning,
validation, cleaning of premises and environmental control, sampling, and inspection). Certain SOPs may be used to supplement product-specific master and batch production documentation.
Turbulent flow
Turbulent flow, or non-unidirectional airflow, is air distribution that is introduced into the controlled space and then mixes with room air by means of induction.
Unidirectional airflow (UDAF)
Unidirectional airflow is a rectified airflow over the entire cross-sectional area of a clean zone with a steady velocity and approximately parallel streamlines. (Modern standards no longer refer to laminar flow, but have adopted the term unidirectional airflow.)
Validation
The documented act of proving that any procedure, process, equipment, material, activity, or system actually leads to the expected results.
Validation master plan (VMP)
VMP is a high-level document which establishes an umbrella validation plan for the entire project and is used as guidance by the project team for resource and technical planning.

 

About Pharmaceutical Guidanace

Mr. Shiv Kumar is the Author and founder of pharmaceutical guidance, he is a pharmaceutical Professional from India having more than 14 years of rich experience in pharmaceutical field. During his career, he work in quality assurance department with multinational company’s i.e Zydus Cadila Ltd, Unichem Laboratories Ltd, Indoco remedies Ltd, Panacea Biotec Ltd, Nectar life Science Ltd. During his experience, he face may regulatory Audit i.e. USFDA, MHRA, ANVISA, MCC, TGA, EU –GMP, WHO –Geneva, ISO 9001-2008 and many ROW Regularities Audit i.e.Uganda,Kenya, Tanzania, Zimbabwe. He is currently leading a regulatory pharmaceutical company as a head Quality. You can join him by Email, Facebook, Google+, Twitter and YouTube

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