Womb to tomb

This article aims to do two key things: Firstly to explain why there is an increasing global need for biotechnology manufacturing, the type of process and equipment it requires, and the advantages in providing facilities for this demand. Second, it aims to give an insight into the key issues and choices that need to be reviewed by a project team when developing a cleanroom for a biotechnology process operation or product, and whether we can learn lessons from other industries.

New biopharmaceutical processes challenge not only our preconceptions of how products work, but also the environments in which we manufacture and refine them in. We can no longer be assumed that all stages of a process will occur within the same company, country, building or cleanroom suite, or that the manufacturing equipment will originate from the pharmaceutical industry. The US, Europe and Asia Pacific regions are all seeing an increase in research investment by governments and corporations into new biopharmaceutical drugs and vaccines, currently around 10% of new drugs are biopharmaceutical, but this is expected to rise to approximately 50% over the next decade. The basic biotechnology processes are simple until we introduce people, product, regulatory and pharmaceutical equipment, and operational/budget requirements into the equation. It then becomes a complex problem to which there are many systems, layouts, technologies and products and the final selections and solutions adopted depends on a detailed analysis of the type of products being manufactured, the process equipment type and the specification used. The production throughputs and scale up ratios, and flexibility required by the cleanroom suite will have a final effect on its size and layout.

Review of biomanufacturing Introduction The new products produced by biopharmaceutical processing are very diverse and being developed in increasing larger numbers. You can also involve several different processes to achieve the same end product specification. There is also more than one method of procurement of the facility, which further complicates the whole design process, and it also requires an integrated solution involving close collaboration between the facility and the process designers. There are many countries competing for the business; Scotland, Ireland, United Kingdom, Netherlands, Singapore and Sweden have all recently announced significant government initiatives to attract more research and development and manufacturing companies to existing or newly developing bioscience centres. Some of these countries have advantages over others because of location, available skill base, and a readiness of their government to grab a bigger slice of the expanding biopharmaceutical industry.

Timetable for approval of biopharmaceutical drugs It takes a typical biopharmaceutical 12 to 15 years from R&D to regulatory approval, at an average cost of $500m (£300million), with only 20% of products entering clinical trials eventually being successful. In Phase I, 80% succeed, in Phase II only 28% succeed, and finally in Phase III only 65% succeed. There were 32 new vaccine approvals in 2000, but this is set to increase dramatically over the next few years, with the largest proportion of these therapies being cancer or cancer related conditions or infectious diseases. The largest product types for these biotechnology medicines in development are Monoclonal Antibodies (59) and Vaccines (98) out of a total of 369 drugs (Source PhRMA 2000). For the current world pipeline for biopharmaceutical products, see Table 1. Status of biopharmaceutical product development There are currently a total of 76 approved biopharmaceutical products on the market, and the top ten of these have annual sales of $9billion. The total industry sales are $31billion. There are 20 to 30 new approvals (products and substances which give an "indication") per year, but this is increasing 3% each year! There are currently 380 products currently in clinical trials and 173 new biotechnology companies were formed in Europe alone in 2000. Therefore there is a big growth potential for biomanufacturing, in both Phase II & III clinical trials and commercial production requirements. The biggest growth potential is in mammalian cell culture, and one product needs 100,000l capacity to support a product on market. There is an anticipated capacity shortfall in cell culture market by 2006 of 500,000 litres (Source J.Odum, Pharmceutical Engineering, Oct 2001). At 0.7m2 per litre this equates to 350,000m2 of facilities by 2006, If you use an approximate "total cost" (equipment + engineering + validation + facility) of $9000 per m2 the industry needs a staggering $3 billion worth of new facilities by 2006, to meet projected demand.

Attractions for providing biomanufacturing There are many new companies and products involved which all require production capacity for clinical trials stage II, III and commercial production. The new companies are most likely to be attracted to clusters of manufacturing facilities, with real value to be added in providing expertise in biomanufacturing. The ideas and science is only 50% of the problem, manufacturing to quality and time is the more important 50%.

Biomanufacturing process requirements Typical bioreactor process The typical bioreactor production stream involves the following stages: working cell bank, seed culture, seed reactors, two inoculum stages, production, harvest then cell separation.

Typical purification process The typical purifcation production stream involves the following stages:- cell separation, four stages of chromatography, ultrafiltration, diafiltration, formulation, filling, freeze drying and primary packing. This is common for transgenic and microbe production, but has low yield for most products( 5 to 20% typical) except for monoclonal antibodies which can be as high as 25 to 50% yield. It has many purfication steps, and involves expensive equipment in high grade cleanroom environments.

Typical process equipment The equipment used in biopharmaceuticals and typically consists of bioreactors, centrifuges, chromatography columns, ultrafiltration units, and freeze driers. These come in varying sizes and can be modular or "built in" design.

Built in versus modular process equipment The decision whether to make a piece of equipment built in or skid mounted needs to be taken and reviewed early in a project as it has a significant on the layouts, programme and costs: l Built In – cleanrooms can be minimised, but this needs early design freeze/selection, can be difficult in new process. You can design into the layout move in routes/installation bulkheads to allow late delivery, but this is more difficult if tem is located in the centre of the facility plan. It does achieve a cleaner facility, with services and pipe work located into technical areas. The equipment becomes a key item for completion of the facility, and it can be more difficult for Factory Acceptance Tests (FAT). l 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 be able to incorporate changes in process steps, which need equipment to be changed to suite a campaign or customer contract. Whenever this is the case, it is very important to think through the installation/ 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 to get the equipment off loaded. The equipment can be easier for FAT, site work is minimised, and it can be broken down into manageable modules, but it comes with cost, cleaning and transportation compromises. 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 that allow maintenance from the non-cleanroom area. This has two benefits, one it minimises the costly cleanroom envelope, and two it minimises the maintenance procedures and costs. This is not always easy to do and there will be limitations caused by the standard designs of equipment provided by pharmaceutical equipment suppliers. Many of these are developing new equipment models. Time researching these at the start of a project, can bring considerable capital and running costs savings, who said it was easy!

Integrated process facility design The design of biopharmaceutical cleanrooms is different from that for primary or secondary pharmaceuticals. Layout in primary facilities is process/piping engineer led, secondary is pharmaceutical engineer/ architect led. Biopharmaceuticals need equal input from process/pharmaceutical engineers, and architect to achieve the best solution. The process design methodology for a biopharmaceutical facility is complicated and has more similarity with primary pharmaceutical facility design than that of secondary facilities. This involves integrating the people and materials flows with the process, the correct room adjacencies to suit both GMP and the most efficient process layout.

Facility requirements for biomanufacturing Methodology for biopharm facility design The facility design methodology involves developing functional adjacency diagrams to suit the User Requirement Specification and process flow diagrams. Then integrating the equipment layouts, defining key working footprint areas and minimum heights, so that the room layouts can be completed. This is further developed/refined with a review of the materials, people flows, air pressure regimes and air flows.

Room classifications The cleanroom classifications in Table 2 are used depending upon the product's exposure to the cleanroom environment, and how close it is to the final purification stages of the process equipment stream, and regulatory requirements by the final drug formulation requirements (ie is it an oral liquid/tablet, inhaled, or injectable drug when taken by patent). The key to minimising production/capital costs is to investigate process equipment options which maximise the use of ISO Class 8 environments and minimise those in ISO Class 5 & 7. Typical classifications: l Utilities, technical area, maintenance Unclassified l Fermenation and upstream processing Grade D/ ISO Class 8 l Purification stages Grade C/ ISO Class 7 l Filling and freeze drying Grade B/ISO Class 5 (at rest) l At point of fill Grade A/ISO Class 5 (laminar flow) Cleanrooms may also have a further regulatory requirement also be designed as a containment suite (virus and potent product manufacture and research). An analysis of the typical product groups require the containment environments in Table 3. These are only a guide, but increasingly some products are requiring a containment level Category 2 to 4,to protect the operator, and a cleanroom environment of 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 / Monoclonal Antibody, a Genetically Modified Organism (GMO) or the safety risks of the substances being processed are not defined.

Layout and flow diagram examples There will be different change regimes required in the facility to suit product exposure and the classification of the processing room. This inevitably means the larger space requirements changing rooms for ISO 5 areas, being in the more expensive areas of the facility. Time spent minimising and rationalising these areas is time well spent. Functional adjacency diagrams are developed and must be designed from the process outwards, and the design team must all understand how the biopharma equipment works and is serviced, and what options there are which might reduce the cleanroom size or make it simpler to service/maintain. Continually review with the process to see if they can be simpler or fewer steps, and most importantly consider move in routes (vertically and horizontally) for process equipment. Cross contamination issues are critical, especially when considering the waste/people/raw materials routes. As a result circulation in a biopharmaceutical facility can be disproportionately high (up to 33-35%) and this can effect the budgeting costs for a project at the early stages.

HVAC pressure regimes The containment requirements can conflict with cGMP requirements, the highest pressure is mainly at the highest grade of room, cascading down to the lowest pressure at the lowest grade room, with most air being recirculated. This is complicated when containing a biohazard (e.g. virus) that is quite a common problem. This requires the opposite pressure regime, so the solution is for the highest pressure to be in the airlock outside the production room so that both the product and the environment outside the suite are protected.

Facility design The key issues in the facility design are: to ensure that there is room for process and building services utilities, HVAC ductwork in the correct areas of the layouts, changing rooms are correctly sized, and located. Flexibility and expandability, and the decision to opt for modular or built in can have a considerable effect on the initial facility costs, and is often the reason for early pre-design budgets being too low. The room height for gravity process drainage is also a key consideration as this can significantly increase the height of the whole facility. The maximum heights allowable by the local planning/building authorities should be checked out early in a front end study, as this may need the process to changed to a non-gravity type which will effect the process equipment costs and increase the cleanroom footprint. Visitor viewing should also be considered in the design for regulatory inspectors, potential customers or for training new staff. Done well this can give the visitor a quick understanding of the process, without out entering higher classification areas and can be a dual use of technical corridor areas, if designed correctly.

Summary The design should be from the inside out, integrate facility closely with the process. You should minimise high grade cleanroom areas, segregate flows, and check the location and specification of process equipment as it has a significant effect on the facility layout and final costs.

Trends Some current common trends for cleanroom design requirements in Europe are: l Flexibility in layout to accommodate easy reconfiguration to match changing business needs l Modular layouts of suites to simplify equipment relocations within a site and between sites l "Cloning" of facilities across country borders to allow dual site production flexibility/security l Increasing demands for bio-pharmaceutical Phase I & II trials material production. l Technology crossovers from other industries e.g. microelectronics are changing some delivery systems and manufacturing equipment. l Increasing use of modular facilities e.g. containerised cleanrooms l Increasing use of modular wall/ceiling panel systems for flexibility l Shorter project delivery times, to get products to market faster

Biography As a chartered architect, he has been involved for over 15 years in design of pharmaceutical, biopharmaceutical cleanrooms (ISO Class 5 to 8), containment suites (ACDP cat 2 to 4), laboratory and process facilities. Previously experience with international design and build/process contractors/architectural practices specialising in pharmaceutical manufacturing facilities/laboratories. Lecturer for the PEAT course Facility Design Module at UMIST, Manchester, UK. He has designed projects in UK, Scotland, Ireland, Netherlands, Italy, Switzerland, Sweden, Denmark, and Japan,and is a member of ISPE, Irish Cleanroom Society, and the RIBA.

This article is a summary of a paper presented at Cleanrooms Ireland at the RDS, 30 May 2002. * Biotechnology Product data for this article was researched by Andrew Provan principal process consultant for Bovis Lend Lease Pharmaceutical. For further information contact Richard Paley tel: +44(0) 161 495 6600; email:richard.paley@eu.bovislendlease.com