Clean Rooms and Air Handling Systems — Design for Compliance

The design, installation, commissioning and qualification of clean rooms heating, ventilation and air conditioning (HVAC) systems is often one of the largest considerations in the design of a new pharmaceutical or biotechnology manufacturing facility. With high running costs (energy associated with the movement, cooling and heating of air) and the potential to impact upon safety and product quality, getting them right

is important for business, safety and good manufacturing practice (GMP) criticality.

The design of the HVAC system will be based upon the clean room suite that it serves, and will be affected by factors such as the number of rooms served, the layout of the rooms, the equipment within the rooms and, most critically from a qualification perspective, the environmental conditions that the rooms must achieve.

Background

The air handling unit helps maintain each room's clean environment by providing an appropriate volume of clean air to each room at the correct temperature and humidity.

The air is filtered by pleated paper filters called high efficiency particulate air (HEPA) filters which, depending upon the classification of the rooms, are located either within the air handling unit or where the air enters each room. Cooling and heating coils are also located within the air handling unit, increasing or decreasing the air temperature to ensure that the room temperatures remain within specification.

Reliable operation of the air handling unit within established limits is critical,¹ not only to prevent product quality from

being compromised by poor air conditioning, but also for the following reasons:

• to prevent cross contamination of products

• to maintain operator safety, where the HVAC is being used for this purpose

• to maintain product safety, where the HVAC is being used for this purpose.

Defining the Requirements

Whereas other services and utilities can be (relatively) easily moved within a building's framework once the building work has been completed, the HVAC is much more integral with the building's fabric, making retrospective modifications much more time consuming and expensive. Getting the specification and design right first time is very important. Figure 1 shows how the costs involved in changing a design increase dramatically as a project progresses.

Figure 1 The cost of change during a project, based on the stage of the project.

What are the problems?

If the design phase is completed without considering the compliance aspects of the clean rooms, then there is a high likelihood of incurring significant time delays and costs during the validation period, as a result of having to make mechanical changes to the installation or revisiting some of

the commissioning work.

Some typical examples of areas where problems can occur as a result of not designing for compliance are highlighted below, together with suggested actions to try to avoid these problems from occurring.

Operating tolerances. Design, commissioning and validation criteria must be determined for GMP-critical parameters such as air change rates, room differential pressures, temperature and humidity.¹ For example, different tolerances may need to be applied at commissioning and validation to ensure that the facility will operate reliably within the validation acceptance criteria limits.

Air filtration. The level of air filtration will vary depending upon the classification of the clean rooms being served. For example, an ISO Class 5 room (Class 100) will require terminal HEPA filters, whereas an ISO Class 8 environment (Class 100000) may be achieved by using a high-grade (non-HEPA) filter within the air handling unit.² To avoid failures during validation integrity testing it is important for the validation and design teams to discuss the in situ test requirements, and to agree upon appropriate grades of air filtration.

Tagging of components. All components and instruments throughout the system should be identified using a clear tagging system. The format of the component tagging must be agreed between the client and the design team during the early stages of the project.

GMP documentation requirements. These requirements (i.e., calibration certificates) are a critical aspect of the design phase that is often overlooked. To ensure that equipment suppliers provide the correct level of documentation, as required by the validation team, documentation requirements should be identified during the design review and be provided to the supplier at the time the equipment order is placed.

Good Design Practices

To guarantee that the finished design will comply with the client's requirements and with appropriate regulatory requirements it is essential to follow a structured approach to the design process.

A prerequisite to the design phase is ensuring that a client representative who is familiar with the manufacturing process is involved throughout, from concept design through to completion of detailed design. If this is not done then expensive modifications to the layout may be required to run the process, resulting in a damaged reputation and possible litigation against the design house.

It is essential that design reviews take place at predetermined milestones throughout the design phase, normally at around 25% and 75% of design completion. These reviews will help ensure that all performance, GMP, safety and other client requirements are being met. These design reviews will challenge the proposed system to ensure that all relevant corporate and international standards are being adhered to. It also provides an opportunity for a validation representative to challenge the design, in terms of operational tolerances and acceptance criteria.

It is also important to perform a GMP impact assessment as part of an appropriately timed design review, as this will help identify those systems, subsystems and components with an actual or potential impact upon product quality. The results of the impact assessment should be used to determine the focus and level of validation required. It will also establish the level of support documentation needed for the validation exercise.

Carefully organized and executed design reviews and GMP impact assessments will help ensure that the validation effort of the project is focussed on the correct areas of the installation, saving resource, money and time. Figure 2 identifies the relative effect upon product quality of the HVAC system relative to other key services and utilities.

Figure 2 The relative effect upon quality of the HVAC system relative to other key services and utilities.

Preparing the Design

The layout of the clean rooms within a new facility is one of the most critical aspects of designing a new pharmaceutical or biotechnology manufacturing building, and is also one of the primary factors influencing the design of the HVAC system. Design of the HVAC can only start in earnest once the room layouts have been determined and their environmental requirements established.

From a technical perspective, the role of the HVAC system is paramount in achieving and maintaining an acceptable manufacturing environment. When designing an HVAC system for a clean room application, two primary objectives must be met:

• To achieve and maintain the quality of the environment as defined within the user requirements.

• To maintain satisfactory temperature and humidity conditions within the clean room. These will vary from facility to facility and will be dependent upon the product being manufactured, the location and corporate standards.

Operating Principles

Figure 3 shows how the volume of air passing through a room from high level to low level helps maintain a clean environment by sweeping away any particulate contamination that may be generated during operations.

Figure 3 Air flow through a typical clean room.

The design air change rates will also be determined by heat gains within each room. Heat gains will come from sources such as lighting, equipment or a process that generates a lot of heat, with a higher throughput of air helping to ensure that the room temperature remains within acceptable limits.

Room temperatures and humidities are often only specified for operator comfort, though in reality excessive temperatures and humidities may have an indirect affect on product quality, because of increased microbiological levels resulting from perspiring operators, leading to microbial vapours and drops. Limits must, therefore, be placed on room temperatures and humidities, regardless of whether the product is sensitive to these parameters.

Figure 4 demonstrates how room differential pressures are designed into each new facility to ensure that a gradient of airflow exists throughout the suite.

Figure 4 Room differential pressure cascade.

In this example, the aseptic receiving and filling rooms are at the highest pressure to maintain a flow of air from these rooms into the less clean change areas and airlocks. These rooms are in turn at a higher pressure than the surrounding unclassified areas, thus providing a cascade of air from the cleanest aseptic rooms towards the unclassified rooms surrounding the facility.

In addition to HVAC design, there are many other potential sources of clean room contamination that relate to the way in which a facility is maintained and operated, some of which are highlighted below:

• Approximately 95% of contamination sources come from personnel, meaning that controlling personnel numbers and flow is of utmost importance.

• Microbiological contamination caused by high moisture levels can be controlled by maintaining appropriate room temperature and humidity conditions, and by cleaning up spillages and leaks.

• Paper and cardboard can provide their own source of microbiological contamination, so limiting the presence of these materials will help maintain a cleaner environment.

• Studies must be performed to determine the most appropriate cleaning agents, while cleaning methods must be documented and, where appropriate, validated as being repeatable and effective.

• Gowning must be appropriate for the clean room classification to try and minimize human contamination levels.

Summary

The HVAC serving clean rooms is deemed a key utility that must be specified correctly to maintain project costs and to comply with GMP requirements.

Prerequisites for correctly designing such an HVAC system are integration with a client representative who is familiar with the client's process requirements, and regular checks against regulatory requirements.

Verification that the design meets client and regulatory requirements should be done using design reviews at regular intervals throughout the design process, with impact assessments being performed to ensure that the correct elements of the design will be validated.

Once the design phase is complete, the project progresses to construction, commissioning and validation. It is just as important to control and monitor each of these three aspects of a project, otherwise all the hard work spent designing a compliant system will have been wasted.

Mark Straker is a senior validation consultant at GxP Ltd, UK

References

1. Rules & Guidance for Pharmaceutical Manufacturers and Distributors, 2002.

2. Clean Rooms and Controlled Environments Standards ISO14644.