Optimal HVAC Systems for Non-Sterile Pharmaceutical Environments: Ensuring Quality and Compliance

Optimal HVAC Systems for Non-Sterile Pharmaceutical Environments: Ensuring Quality and Compliance

In the pharmaceutical industry, maintaining a controlled environment is crucial to ensure product quality, safety, and regulatory compliance. HVAC (Heating, Ventilation, and Air Conditioning) systems play a vital role in non-sterile pharmaceutical facilities by providing appropriate temperature, humidity, and air quality control. These systems help prevent contamination, control particulate levels, and create a comfortable working environment for personnel. In this blog post, we will explore the importance of HVAC systems in non-sterile pharmaceutical environments, their key components, design considerations, and best practices for optimal performance and regulatory compliance.

I. The Importance of HVAC Systems in Non-Sterile Pharmaceutical Environments

A. Regulatory Requirements:

1. Compliance with Good Manufacturing Practices (GMP): Discuss how HVAC systems are essential to meet GMP requirements, ensuring a controlled environment for pharmaceutical manufacturing, packaging, and storage.
2. International Standards: Highlight the relevance of international standards, such as ISO 14644 and EU GMP Annex 1, in defining HVAC system requirements for non-sterile pharmaceutical facilities.

B. Contamination Control:

1. Particulate Control: Explain how HVAC systems help control and minimize particulate levels, ensuring a clean and particle-free environment that prevents product contamination.
2. Microbial Control: Discuss the importance of HVAC systems in controlling microbial growth, and preventing the introduction of bacteria, molds, or other harmful microorganisms.

C. Environmental Parameters:

1. Temperature Control: Explain the significance of HVAC systems in maintaining consistent and controlled temperatures within pharmaceutical facilities, ensuring product stability and integrity.
2. Humidity Control: Discuss the importance of controlling humidity levels to prevent moisture-related issues, such as degradation of products, microbial growth, and stability concerns.

II. Key Components and Design Considerations for HVAC Systems

A. HVAC System Components:

1. Heating Systems: Explain the different types of heating systems used in HVAC systems, such as boilers, electric heaters, or heat pumps.
2. Ventilation Systems: Discuss the role of ventilation systems in providing fresh air exchange, removing airborne contaminants, and controlling odor and humidity.
3. Air Conditioning Systems: Explain the importance of air conditioning systems in controlling temperature and humidity levels, providing comfort for personnel, and product stability.
4. Filtration Systems: Discuss the various types of filters used in HVAC systems, including pre-filters, high-efficiency particulate air (HEPA) filters, and activated carbon filters.

B. Design Considerations:

1. Facility Layout and Zoning: Explain how facility layout and zoning considerations impact HVAC system design, ensuring appropriate segregation of different areas based on environmental requirements.
2. Airflow and Pressure Control: Discuss the importance of designing HVAC systems with proper airflow distribution, air balancing, and differential pressure control to prevent cross-contamination and maintain controlled environments.
3. Filtration Efficiency and Maintenance: Highlight the significance of selecting appropriate filters and establishing a robust maintenance program to ensure optimal filtration efficiency and minimize contamination risks.

C. Energy Efficiency and Sustainability:

1. Energy Management: Discuss the importance of energy management strategies, such as variable speed drives, energy recovery systems, and efficient equipment selection, to optimize HVAC system energy consumption.
2. Green Initiatives: Explain how incorporating sustainable practices, such as using eco-friendly refrigerants, reducing energy consumption, and implementing smart controls, contributes to environmental sustainability.

III. Best Practices for HVAC System Operation and Maintenance

A. Regular Maintenance and Calibration:

1. Preventive Maintenance: Discuss the importance of regular preventive maintenance activities, such as filter replacement, cleaning coils, and inspecting ductwork, to ensure HVAC system performance and longevity.
2. Calibration and Validation: Explain the significance of periodic calibration and validation of HVAC system sensors, controls, and monitoring devices to ensure accurate measurements and compliance with regulatory requirements.

B. Airflow Monitoring and Control:

1. Airflow Monitoring: Discuss the importance of implementing airflow monitoring systems, such as differential pressure sensors or velocity sensors, to ensure proper airflow rates and capture any deviations.
2. Control Strategies: Explain the use of control strategies, such as variable air volume (VAV) systems or airflow balancing, to maintain appropriate airflow rates and optimize energy consumption.

C. Environmental Monitoring and Alarms:

1. Continuous Monitoring: Highlight the significance of implementing continuous environmental monitoring systems to track temperature, humidity, pressure differentials, and particle levels.
2. Alarm Systems: Discuss the importance of setting up alarm systems to promptly alert personnel of any deviations from defined environmental parameters, allowing for immediate corrective actions.

IV. Compliance and Validation of HVAC Systems

A. Qualification and Validation:

1. Design Qualification (DQ): Explain the process of design qualification, which involves evaluating the design and functionality of HVAC systems to meet user requirements and regulatory guidelines.
2. Installation Qualification (IQ) and Operational Qualification (OQ): Discuss the importance of IQ and OQ activities, which involve verifying that the HVAC system is installed correctly, functions as intended, and meets performance specifications.

B. Risk Assessment and Mitigation:

1. Risk Assessment: Explain the importance of conducting risk assessments to identify potential risks, such as equipment failures, temperature excursions, or air contamination, and implementing appropriate mitigation strategies.
2. Standard Operating Procedures (SOPs): Discuss the significance of developing SOPs to define proper operation, maintenance, and corrective actions for HVAC systems, ensuring consistent performance and compliance.

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

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 about 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 systems are product protection, personnel protection, and environmental protection.

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
• The 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.

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 concerning 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 a 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, 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 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 protect 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 the 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 utilizing 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.

Once the system has been designed and qualified with a specific layout for operators and processes, this should be maintained by 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.

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 concerning the areas surrounding it, with 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 airflow 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), 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 the 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 airflow 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 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 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.
• 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 using 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 using 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 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.

Pharma More Jobs and post Please click here