By Robert McIlvaine, President, The McIlvaine Company
The pharmaceutical/biotechnology industry is the second largest consumer of cleanroom space. This segment has grown steadily, unlike the electronics segment, which has grown in spurts. Pharmaceutical products comprise tablets, capsules, liquids packaged in various ways, and injectables (parenterals). The focus of concern in the pharmaceutical industry is on contamination with such viable particles as bacteria and viruses whose own biological activity may cause the final pharmaceutical product to have unintended effects.
The maximum distribution of the viable particles of concern seems to occur in the 0.3 μm size range. The smallest airborne bacterium likely to challenge a filter is approximately this size, since viable bacteria occur infrequently as individual organisms. Instead, they tend to cluster as colony forming units (CFUs). Viruses, while much smaller, tend not to be mobile unless they are attached to a host, and the most mobile host organisms have also been found to cluster in the 0.3 μm range.
In the rare instances where they do occur independently, no known filter technique is effective against all viruses, due to their very small size (0.003 μm to 0.05 μm). However, combinations of devices, such as ultraviolet light in conjunction with filters or electrostatically charged filters, are options for virus destruction.
Many pharmaceutical products cannot be subjected to a final “terminal” sterilization step because they are not heat stable. These products must be produced by 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.
Producing sterile components is increasingly challenged by the fact that there is no nondestructive means of testing the final product once it is packaged. Sterility rates are inferred from periodic samplings in which an entire batch of product is tested. In practice, “sterility” in pharmaceutical operations is interpreted to mean that there is a one-in-a-million chance that a terminally sterilized product is contaminated, and a one-in-one-thousand chance that an aseptically produced product is contaminated.
Standard practice in the pharmaceutical industry is to maintain Class 100 (ISO Class 5, metric class M3.5) conditions in the “critical areas,” locations in which open, sterile containers are exposed to the environment. Although Class 100 conditions do not need to be maintained throughout the entire aseptic facility, it is important that they be maintained in these localized critical areas. The use of isolators is one means of achieving localized areas of greater cleanliness.
Trends
There are a number of industry trends that are changing cleanroom requirements. One is the use of isolators. Isolation technology can reduce the cost of pharmaceutical/biotech cleanrooms. Large-scale cleanrooms can be replaced by rooms with various smaller areas utilizing isolation techniques. This technology is now being applied in many pharmaceutical production facilities.
Isolation technology removes the people from the cleanroom production area, but to do so there must be an automated method for moving the product in an out of the isolator. 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. There are instances in both small- and large-scale pharmaceutical production where direct interface of the isolator with some particular process is the optimum method of transfer. The freeze dryer is a typical example.
Another trend is the increased expenditure on cleanrooms in pilot plants. Until recently, construction costs for pilot projects were typically $10 to $50 million. Today, many are being built in the $300 million range. The pilot plants are usually owned by the drug maker’s research arm and are often as large as the final production plant. The journey from drug development to commercial introduction can take 10 to 15 years and cost $500 million.
Outsourcing is still another trend. Production of pharmaceutical bulk actives and intermediates is being outsourced to facilities designed to meet the stringent standards of current Good Manufacturing Practices (cGMP), allowing drug makers to quickly test and scale up drug production without having to make an initial investment in a new plant and new equipment.
Biotechnology is moving from the small pilot-type facility to large production facilities with substantial cleanrooms.
Markets
The U.S., including Puerto Rico, accounts for 40 percent of the world’s pharmaceutical and biotech cleanroom space and its consumables purchases (see Figs. 1 and 2).
Between 1990 and 2004, R&D investment in the United States grew 4.5 times, while in Europe it only grew 2.7 times. Between 1993 and 2003, the U.S. market grew by 11.9 percent per annum, well ahead of Europe (weighted average growth of 7.3 percent). According to IMS Health data, 70 percent of sales of new medicines marketed since 1999 are generated on the U.S. market, compared with 19 percent on the European market.
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The U.S. pharmaceutical and medicine manufacturing industry consists of about 2,500 plants located throughout the country. These include establishments that make pharmaceutical preparations or finished drugs; biological products, such as serums and vaccines; bulk chemicals and botanicals used in making finished drugs; and diagnostic substances.
The U.S. employed 300,000 people in the pharmaceutical industry. Of these, 90,000 are production employees.
Puerto Rico has the highest concentration of pharmaceutical manufacturing anywhere in the world. It accounts for 17 percent of the total U.S. pharmaceutical cleanroom space. There are more than 60 plants, employing 27,000 workers. In recent years, large investments by Eli Lilly and Amgen have boosted the amount of cleanroom space.
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China is a fast-growing pharmaceutical market, having an average rate of growth of 10 to 12 percent. China is the eighth largest pharmaceutical market in the world with more than US$8 billion total sales in 2004. More and more overseas companies are coming to China to promote their products or to set up joint-venture manufacturing in China.
The pharmaceutical market in China is dominated by its nonbranded generic industry, which operates with basic technology and simple production methods. Domestic pharmaceuticals are not as technologically advanced as western products, but nonetheless occupy approximately 70 percent of the market in China. Domestic companies are mainly government-owned and fraught with overproduction and losses. The Chinese government has begun consolidating and upgrading the industry in an effort to compete with foreign firms.
There are more than 6,000 pharmaceutical factories in China. Since 1998, pharmaceutical manufacturing has been steadily increasing 8.4 percent annually.
China has the potential to become the largest pharmaceutical R&D base in the world. In recent years, more and more western pharmaceutical enterprises, such as GlaxoSmithKline, Roche, Novo Nordisk, and others, have come to China and set up R&D centers. Twenty world-leading pharmaceutical companies have established joint-venture manufactories in China.
The Indian pharmaceuticals sector meets almost 95 percent of that country’s pharmaceutical needs. The size of the Indian pharmaceutical industry is estimated at $8.7 billion. The domestic pharmaceutical output has increased at a compound growth rate (CAGR) of 13.7 percent per annum. Globally, the Indian industry ranks fourth in terms of volume and thirteenth in terms of value.
The Indian pharmaceuticals industry has over 20,000 plants with 200 medium- and large-sized research and development-based pharmaceutical companies, including multinationals, government-owned and Indian private companies. In addition to these large companies, it is estimated that there are 10,000 smaller, licensed generic manufacturers but only around 3,000 of these companies are operational.
The Indian Parliament finally approved India’s long-awaited product patent legislation in March 2005. The Indian Patents Third Amendment Bill, 2005, establishes product patent protection for pharmaceuticals in India.
Many global pharmaceutical majors are looking to outsource manufacturing from Indian companies, which enjoy much lower costs (both capital and recurring) than their western counterparts. Many Indian companies have made their plants cGMP-compliant and India also has the largest number of USFDA-approved plants outside the U.S.
Asia will continue to grow and increase pharmaceutical cleanroom market share at the expense of Europe.
The pharmaceutical industry will continue to be an important and steadily growing segment of the cleanroom industry. Further, new product and manufacturing trends will require adaptation by cleanroom suppliers.
Robert McIlvaine is president and founder of the McIlvaine Company, Northfield, Ill. The company first published “Cleanrooms: World Markets” in 1984 and has since continued to publish market and technical information for the cleanroom industry.