Heating, ventilation and air-conditioning systems for non-sterile pharmaceutical products-WHO

Heating, ventilation and air-conditioning (HVAC) play an important role in ensuring the manufacture of quality pharmaceutical products. The good manufacturing practice (GMP) requirements for the prevention of contamination and cross-contamination are an essential design consideration of an HVAC system. A well-designed HVAC system also provides for protection of the environment and the operators as well as comfortable working conditions. 

These guidelines mainly focus on recommendations for HVAC systems used in facilities for the manufacture of non-sterile dosage forms, which include tablets, capsules, powders, liquids, creams and ointments. The general HVAC system design principles contained in these guidelines may, however, also be applied to other dosage forms.

HVAC system design influences architectural building design and layout, for example, with regard to airlock positions, doorways and lobbies. These in turn have an effect on room pressure, pressure differentials, pressure cascades, contamination and cross-contamination control. Therefore, the design of the HVAC system should be considered at the initial design stage of a pharmaceutical manufacturing plant.

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 and instruments. A comprehensive science- and risk-based approach should be followed throughout the life-cycle of an HVAC system, including its design, qualification and maintenance. Risk assessment is, however, not a substitute for GMP.

These guidelines focus primarily on GMP for the design, qualification, management and maintenance of HVAC systems in facilities for the manufacture of non-sterile dosage forms. They are intended to complement the guidelines on GMP for pharmaceutical products and should be read in conjunction with the parent guide. The additional standards addressed in these guidelines should therefore be considered supplementary to the general requirements set out in the main principles guide

Most of the system principles described in these guidelines may also be considered in facilities manufacturing other dosage forms and products, and finishing processing steps for active pharmaceutical ingredients (APIs). Additional, specific requirements may apply for air-handling systems for pharmaceutical products containing hazardous substances, sterile products and biological products. 

1. Premises

1.1 The manufacture of non-sterile pharmaceutical products should take place in a controlled environment, as defined by the manufacturer. 

1.2 The design of the HVAC system should be closely coordinated with the architectural design of the building.

1.3 Infiltration of unfiltered air into a manufacturing facility should be prevented as this can be a source of contamination.

1.4 Manufacturing facilities should normally be maintained at a positive pressure relative to the outside, to prevent the ingress of contaminants. Where facilities are to be maintained at negative pressures relative to the outside, special precautions should be taken to mitigate any risks (see (3)).

1.5 Areas for the manufacture of products, especially where materials and products are exposed to the environment, should be of an appropriate level of cleanliness. The level of air cleanliness for different areas should be determined according to, but not limited to, the products manufactured, the process used and the products’ susceptibility to degradation. Where a clean room classification is specified, the manufacturer should state whether the classification is rated for the “as-built”, “at-rest” or “operational” condition.

1.6 HVAC systems should ensure that the specified room conditions are attained, for example through heating, cooling, air filtration, air distribution, airflow rates and air exchange rates. 

1.7 Any area where pharmaceutical starting materials, products, primary packing materials, utensils and equipment are exposed to the environment should have the same level of cleanliness or classification as the area in which the products are produced.

1.8 Appropriate design and controls for the premises and HVAC systems should be in place to achieve containment, cleanliness and the appropriate levels of protection of the product, personnel and the environment. Note: For facilities where the highest level of containment is a requirement, refer to the guidance in WHO good manufacturing practices for pharmaceutical products containing hazardous substances.

1.9 Containment, cleanliness and protection may be facilitated through, for example:

■ correct building layout;

■ building finishes;

■ the use of airlocks such as personnel airlocks (PAL) and/or material airlocks (MAL);

■ pass-through hatches (PTH);

■ change rooms and passages;

■ sufficient pressure differentials.

1.10 Detailed schematic diagrams should be maintained, indicating, for example, air supply and air return, room pressure differentials and airflow directions.

1.11 Where possible, personnel and materials should not move from a higher cleanliness zone to a lower cleanliness zone and back to a higher cleanliness zone. Where this is unavoidable, risks should be identified and controlled. 

1.12 The final change room should be at the same cleanliness level (at rest) as the area into which it leads. 4.13 Where appropriate, such as where the simultaneous opening of airlock doors might lead to a cross-contamination risk, airlock doors should not be opened at the same time. In such cases, controls such as interlocking systems, warning systems and procedures should be implemented. 

1.14 Swing doors should normally open to the high-pressure side and be provided with self-closers. Exceptions to the door swing direction should be justified and may include for fire escapes or other health and safety measures. In these cases, door closer mechanisms should be carefully controlled and other controls should be in place to prevent any risk.

1.15 Sampling, weighing and dispensing areas should be appropriately designed to provide the required levels of containment, operator protection and product protection.

1.16 Sampling, weighing and dispensing should be performed under the same environmental conditions as specified in the areas for the next stage of processing of the product.

1.17 Factors such as airflow should not disrupt the accuracy of balances.

1.18 The position of the operator, equipment and containers should not obstruct airflow patterns and result in risks.

1.19 Once an area is qualified with a specific layout for operators, equipment and processes, this configuration should be ensured during routine activity.

1.20 Return and exhaust filters and grilles selected and installed should be appropriate and their design should facilitate cleaning and maintenance.

1.21 The impact and risk to the HVAC system should be considered when changes are planned to an existing facility. This includes upgrades and retrofitting of facilities. 

2. Full fresh air systems and recirculation systems

2.1 Full fresh air or recirculation type HVAC systems may be used. Fresh air should be adequately filtered to remove contaminants. Where recirculation systems are used, there should be no risk of contamination or cross contamination.

2.2 HEPA filters may be installed (in the supply air stream or return air stream) to remove contaminants and thus prevent cross-contamination. The HEPA filters in such an application should have an EN 1822 classification of at least H13 or equivalent.

2.3 HEPA filters may not be required to control cross-contamination where evidence that cross-contamination would not be possible has been obtained by other robust technical means, or where the air-handling system is serving a single product facility.

2.4 The amount of fresh air intake required should be determined. As a minimum, the following criteria should be considered:

■ sufficient volume of fresh air to compensate for leakage from the facility and loss through exhaust air systems;

■ operator occupancy;

■ regional or national legislation.

2.5 Air that might be contaminated with organic solvents or highly hazardous materials should normally not be recirculated.

2.6 The need for and the degree of filtration of the exhaust air should be considered based on risk, exhaust air contaminants and local environmental regulations.

2.7 Where energy-recovery wheels are used in multiproduct facilities, controls should be in place to ensure that these do not become a source of cross contamination.