The key to success

Developing a cleanroom for an existing or new pharmaceutical process, operation or product can cause problems for the project team. Final solutions depend on a detailed analysis of the type of products manufactured, process equipment type and the specification used. Introducing the elements of people, product, regulatory and pharmaceutical equipment, as well as operational budget requirements, further complicates the equation. Production throughputs and flexibility required by the cleanroom suite will also have an effect on its size and layout. Different types of cleanroom require different disciplines to lead the design process. 1. In primary pharmaceutical facilities, the process engineering equipment and piping layouts dictate design, because they are the key part of the manufacturing process. The cleanroom is likely to be a small offloading, vessel charging or dispensing suite. The process is the lead discipline.

2. In secondary pharmaceutical facilities, the architectural room layouts and air environment is the "manufacturing vessel" in which products and people are moved around in. The architectural or mechanical services are the lead disciplines.

3. In biopharmaceutical facilities, both the process equipment, and room layouts and people flows are equally important to the process. So processes and architecture are the lead disciplines for an integrated solution. When embarking on a project, it is essential that all relevant personnel are involved in the early stages of a design. This avoids reworking the design layouts later on as there is ownership by the whole company and costly errors are minimised due to the useful input from a wider team. The team develops the initial user requirement specification (URS). This is a short definition of the processes, equipment, operations, capacities and environmental criteria for the new cleanroom.

4. In containment cleanroom facilities, the architectural room layouts and the HVAC environment are paramount to the fundamentals of a contained suite of laboratory cleanrooms. Both architectural and HVAC disciplines take the lead to produce an integrated solution. When embarking on this type of project, it is fundamental that the project sponsor has all relevant personnel in place, so the design team can gain a clear understanding of the task ahead. The team will bring together a collective and collaborative URS from which the design can begin.

Cleanroom modules 5. In mobile cleanrooms (modules), the facility architect and the process and HVAC disciplines will plan out and define the operation of the ergonomic space available. These cleanrooms are usually self-supporting welded steel frame units with walk-on ceilings containing integrated HEPA filters and light fixtures. They are completely self contained and are provided with all the characteristics of a traditional cleanroom. In the URS, the designer needs to review the flows around the cleanroom to assess the optimum layout for regulatory compliance (CGMP), efficient operation and to minimise cross contamination. It is easy to simplify all the flows in new facilities, but difficult in retrofit situations where compromises may need to be made due to space or cost constraints. Procedures and controls may have to be put in place to avoid cross contamination where waste, people, raw materials and finished goods are sharing single corridors. These items become reliant on SOPs for procedural compliance and are hard to maintain. The URS for a facility needs to define which equipment is to be used, what options it has and, if it is a new process, what areas of the process still need to be developed. This enables the design team to anticipate and accommodate equipment changes during the design process. The decision whether to make a piece of equipment built in or skid mounted needs to be taken early in a project as it has a significant impact on the layouts, programme and costs.

6. Built in – small cleanrooms can be achieved but need early design selection, which can be difficult in a new process. Layout move-in routes or installation bulkheads can be designed in to allow late delivery but this is more difficult if the item is located in the centre of the facility plan. Wherever possible equipment should be located to edges of the cleanroom footprint.

7. Modular – "skid mounted" or free-standing equipment may be required by a facility because one or more process steps are being developed, or the facility needs to incorporate changes in process steps that need equipment to be changed to fit a campaign or customer contract. Whenever this is the case in primary, secondary or bio-pharmaceuticals cleanrooms, it is important to think through the installation and removal route. Corridor widths may need to be increased, roof openings designed in, removable walls in the shell building or cleanroom need to be included and access around the building is required to get the equipment off loaded. The key issue in layout design is to maximise the technical and lower classification areas around the main cleanroom suite by locating and specifying process equipment so it can be located in positions which allow maintenance from the non cleanroom area. This has two benefits; firstly it minimises the costly cleanroom envelope, and secondly it minimizes the maintenance procedures and costs. This is not always easy and there will be limitations caused by the standard designs of equipment. Many pharmaceutical suppliers are developing new equipment models, so research these at the start of a project, as it can bring considerable capital and running costs savings. The layout should keep personnel and materials separate. When planning cleanrooms of the higher classifications (class 5 and class 7) sufficient space needs to be allowed in the layout for incorporating multiple change steps, and in the case of some class 5 suites, and containment level 3 and 4 suites, separate exit and entrance routes to stop cross contamination of clothing. In smaller higher classification suites a high proportion of the layout can be taken up by changing rooms and materials airlocks and transfer hatches, so it is important to cost these out in any project approval budget at conceptual stage.

Product dictates As a general guide the main product groups dictate which cleanroom environment is required. A detailed assessment should be made with production, QA personnel and regulatory authorities, and defined before the cleanroom design starts, predominantly at FED stage to determine the required type as it will impact on the specification and operational costs of the facility, and ultimately the profitability of the product. In addition, containment cleanrooms come under scrutiny from a range of different guidelines, such as ACDP, ACGM, DEFRA and HSE. It is important when planning containment cleanroom facilities, especially CL3 and CL4, that more stringent guidelines are acknowledged as they will reflect in the cost of the cleanroom. Cleanrooms may have to also be designed as containment suites. Increasingly some products are requiring a containment level Category 2 to 4 to protect the operator, and a cleanroom environment or ISO 5 to 8 to protect the product. These tend to occur more often when part of the manufacturing process is novel or the product is a virus or monoclonal antibody, or the safety risks of the substances being processed are not defined. A high proportion of new bio-pharmaceutical products are of this type. There are four basic types of cleanroom construction (see Table 2). Generally the more flexibility and faster construction time you want will dictate types 3 and 4 and if economy is required then 1 and 2, however these come with time penalties and less flexibility in the construction phase. The type of wall construction needs to be defined early in a project (FED), as it affects the total project cost, timetable, and engineering and detailing costs. Validation is the process of providing documented evidence that a facility, mechanical service or item of equipment will perform consistently as intended. It should be considered an integral part of the construction process for a pharmaceutical cleanroom facility. Validation requirements should be properly costed at 5-10% of the facility costs and planned for at each stage of the design process. Time and costs can be reduced by fully integrating the validation team with design, construction and commissioning teams.

Validation procedure Five steps can be followed to integrate validation into the design of a cleanroom: 1. A validation master plan (VMP) should be available early in the design process. This document will include the scope of the validation, items to be validated along with acceptance criteria and risk assessments. 2. Design qualification/review is a documented review of the design to conform with operational, regulatory and user expectations. This can significantly reduce mistakes at subsequent stages. 3. Installation qualification (IQ) ensures that all critical aspects of the facility are as specified and correctly installed, such as room finishes and filter integrity tests. 4. Operational qualification (OQ) ensures that all critical items operate as intended, ie. airflow rates and differential pressures. 5. Performance qualification (PQ) for a facility verifies the ability to maintain the required considerations, ie. particulate cleanliness, temperature/humidity profiles. Early in the scoping and design phase of project the type of procurement route needs to be reviewed by the design team. This will have an effect on the level of detail design done by the project team and by the selected cleanroom installation contractor. This decision can affect the whole project costs. The alternatives are outlined in Table 3, but there are subtle variations on these being developed by the construction community. It is advisable to carry out a concept study or front-end engineering study to establish accurate costs as they vary considerably with facility specification, sizes of rooms, and layout and location. A common mistake made by many companies is to assume that the m2 price from a previous project can be used for budgeting purposes for capital approval only to find that it is inadequate. This will then force the design team to design and specify within the budget available. Another mistake made by companies is that a design, layout or specification that worked in one country still works in another. This is common in projects where the facility or process is copied to other locations. This can have a minor or major effect on the design or costs if not included early into the design. Examples of this include: 1. In the UK, facilities do not have daylight entering cleanrooms, but in most mainland European countries they must. This affects the shape of the cleanroom suite. 2. Fire escape travel distances differ between European countries, as do arrangements of doors to escape stairs. 3. There are different building codes, even within the UK. Europe, Wales, Scotland and England have subtly different building regulations and planning procedures, which effect start on site times. 4. A vertical process using gravity in one country, may not work in another because the ground conditions and local height restrictions do not allow tall structures – the process then has to be redesigned. Current trends for cleanroom design requirements in Europe call for greater flexibility in layout to accommodate easy reconfiguration to match changing business needs and modular layouts of suites to simplify equipment relocations within a site and between sites. In addition to this, the cloning of facilities across country borders to allow dual site flexibility and increasing use of modular facilities and modular panel systems for flexibility and shorter project delivery times means that cleanroom design has to get smarter to meet these needs.

Bovis Lend Lease T: +44(0)161 495 6600 Steve.fare@eu.bovislendlease.com