Bob McIlvaine

There is an increasing need for clean room technology in the pharmaceutical and biotechnology industries. The bio/pharmaceutical industry is the second largest consumer of clean room space and, unlike the electronics segment - which has grown in spurts - this sector has grown steadily. The focus of concern in the pharmaceutical industry is on contamination, wherein the biological activity of viable particles such as bacteria and viruses may cause the final pharmaceutical product (tablets, capsules, packaged liquids and parenterals) to have unintended side-effects. Many pharmaceutical products cannot be subjected to a final, "terminal" sterilization step because they are not heat stable. These products must be produced using an aseptic filling process, in which the separate components of the product are sterilized in individually appropriate ways and assembled under conditions approximating sterility as closely as possible.	

The HEPA filtration system in pharmaceutical clean rooms presents some distinct challenges. A terminal filtration system, in which ducts connect the individual HEPA filters to the air handling system, is the most common choice for Class 1000-100000 clean rooms. It is critical that the ducting does not contain any acoustic lining that could harbour microbial growth. In situations where a plenum configuration is selected, the sealing technique becomes a critical consideration. The gel sealant, popular in other applications - such as animal research and the production of medical devices - since the 1960s, has been less enthusiastically received by the pharmaceutical industry because the U-channels constructed to seat the filter units make sanitizing difficult. 	

Table I:  Percentage market share of the clean room industry in Europe.	

The use of isolation technology can reduce the cost of clean rooms in a variety of industries such that large-scale clean rooms can be replaced by rooms with various areas utilizing isolation techniques. Isolation technology is now being applied in production facilities at pharmaceutical companies. 				

The flow pattern within the volume of the isolator demands very careful consideration. It may need to be laminar in some specialized applications where high particle burdens are generated but, in general, turbulent flow will provide the desired conditions - although there is an argument that laminar flow will remove the need to sterilize the isolator. The important factor is that the flow should purge the entire volume, leaving no dead spaces, so that particles are steadily swept away to the exhaust filter. For fast transfer of items to and from an isolator, the special rapid transfer port solves the problem of waiting while items are sterilized on the way in, or decontaminated on the way out. 	

Aseptic work is probably the largest single application of isolation technology and thus the sterilization of the interior of isolators and their contents is critical. Most sterile processes will need to be validated before products can be marketed, and thus isolator users must be able to demonstrate reliable and reproducible sterilization cycle results. Biotechnology is the fastest growing segment of the industry and there is a great deal of potential growth in clean room sales to this sector. This industry requires clean rooms not only to protect the product, but also to protect the worker. For example, approximately 5% of biotechnology plants currently utilize cells or products known to be pathogenic or derived from genetic engineering techniques. Needs include safety cabinets, benches and complete clean rooms. 	

Applications for isolator technology in biopharmaceutical manufacturing include maintenance of cell culture banks and the initial steps of seed culture expansion. Isolator systems can also be used for fermentation operations done at working volumes of only a few litres. 	

Purification equipment such as chromatography columns and ultrafiltration membranes can be located within an isolator. For larger-scale systems it is possible to obtain isolators that enclose a volume of several hundred cubic feet. 	

Filling of sterile bulk is often the first step in a process in which a manufacturer makes the claim of sterility for a product. At this point, a bulk sterility test is conducted by gowned employees in a Class 100 cabinet or enclosure. If filling of a product into final dosage forms is done on-site, the product can be transferred to a formulation area within a transfer isolator. 	

Compounding is often done under Class 10000 conditions. In many cases, a product is held under clean, but not aseptic, conditions until final filtration. The use of isolation technology makes compounding much safer and allows samples to be taken with complete protection from human-borne contamination. 	

Aseptic processing of unpreserved biologicals is a risky operation. Isolators have been used in Europe for aseptic processing for several years and validation studies have indicated that these systems are capable of attaining contamination rates of zero during long periods. 	

Bio/pharmaceutical clean room revenues in Europe represent more than 25% of the world's clean room expenditure. Pharmaceuticals still provide by far the largest contribution to the European trade balance in high-technology, research and development-intensive sectors. And yet Europe's drugs sector, which led the world for much of the last century, is losing ground compared with other regions. Former industry leaders such as Bayer of Germany have lost market share. Others such as the Anglo-Swedish AstraZeneca and Novartis of Switzerland have remained in the top tier only by virtue of mergers. 				

In 2000, European pharmaceutical and biotechnology firms spent $128 million on new clean rooms. By comparison, the expenditure for the entire European industry for new clean rooms was $542 million. By 2006, the room revenues in the pharmaceutical sector will increase to $178 million compared with $717 million in all sectors. Clean room consumables purchases by European pharmaceutical companies will rise from $121 million in 2002 to $151 million in 2006.	

Europe still accounts for approximately 27% of the global market. However, it is not really a single market. In health care, each member state operates its own pricing and regulatory framework, breaking the drugs market into smaller fragments. 				

Europe is competing in a rapidly growing biotechnology market worldwide. The major players in mammalian cell manufacturing are DSM, Boehringer Ingelheim, GlaxoSmithKline and Lonza. Global mammalian cell capacity will need to grow by 400% by 2006 to meet forecast demand, noted Lonza, and DSM recently confirmed a 60000 L/year capacity expansion.	

France and Germany are the two largest European purchasers of pharmaceutical clean rooms. Table I displays the market share for individual Western European countries. Each number is a percentage of the world market in 2000. So, the pharmaceutical market in Austria will grow from 0.5% of the world 2000 market to 0.67% of the world 2000 market in 2006.	

In the UK, the pharmaceutical industry will spend $12 million on new clean rooms in 2003. Employment in pharmaceutical clean rooms will rise to 4900 people, occupying just less than 500000 sq ft of clean room space.	

In the British biotech sector, consolidation is looking increasingly likely. Xenova, Britain's biggest oncology specialist, has only a modest market capitalization. UK biotech companies include:	

More than 400 life science companies are now located in Scotland, ranging from multinational subsidiaries such as GlaxoSmithKline (Irvine), Roche (Dalry), Quintiles Transnational Corp. (Edinburgh), Q-One Biotech (Glasgow) and Inveresk (Tranent), to home-grown companies such as PPL Therapeutics (Midlothian), Scotia (recently acquired by the Singapore company Blue Dot and renamed QuantaNova) and Strakan (Galashiels).	

There have also been at least 20 new companies formed during the last 2 years, including Ardana Bioscience (Edinburgh), Crusade Laboratories (Glasgow), Cypex Ltd (Dundee) and Psychiatric Diagnostics (Inverness).	

Purchases of new rooms by Italian pharmaceutical and biotechnology companies in 2003 will be close to $11 million. Italy has been a successful supplier to world pharmaceutical markets; in 2001, some 85% of active ingredients and intermediates sales, estimated at $2.8 billion, was exported. In 2002, a 2.5% increase in production volume was achieved following a 5.5% growth in 2001.	

Sweden and Denmark are relatively small clean room markets. Copenhagen and its hinterland, plus Skane county in neighbouring Sweden, are now home to one of Europe's biggest clusters of biotech and pharmaceutical companies. Medicon Valley, as the region is known, houses the headquarters of more than 60% of Scandinavia's pharmaceutical and biotechnology companies.	

Sales of new clean rooms are anticipated to be approximately $1 million in 2003 in the Finnish pharmaceutical sector. Today, one in ten European biotech companies is Finnish, which places the country sixth in Europe after the UK, Germany, France, The Netherlands and Sweden. There are more than 100 biotech companies in Finland at present, about three-quarters of which were created during the last decade.	

Room revenues in the French pharmaceutical clean room sector are slated to rise to $19 million in 2003. Employment in pharmaceutical clean rooms will increase to 7330 personnel and more than 730000 sq ft of clean room space will be in operation.	

Germany will be a slightly larger market. Room sales in 2003 will be $21 million, employing 8600 people who will be working in 790000 sq ft of pharmaceutical clean room space. In 2003, an additional 90000 sq ft will be added.	

Articles

In the pharmaceutical and biotechnology sectors, the clean room business is flourishing. Accounting for approximately 25% of the world's clean room expenditure, Europe's drug manufacturing industry is using these facilities to produce an increasing amount of biologics and biopharmaceuticals, and meet the strict legislative requirements for aseptic processing. This article reviews the current and future state of the market for clean rooms in Europe and comments on their applications.