John Challenger, non-executive Chairman, WH Partnership, looks back at how cleanroom design has developed over the past 40 years and at the current drivers in the pharmaceutical and biotechnology sectors that might affect designs in the future
Figure 1: WHP client TC Biopharm. The clinical manufacturing facility at Maxim Park, Glasgow, uses patients’ own immune cells grown in culture to target cancer. Constructed to comply with stringent UK GMP regulations, the 3,500ft2 facility took just 12 weeks to build from start to finish. It includes two cleanrooms, QC suites and development labs designed to support the manufacture of clinical grade product. The facility has just been granted a UK Medicines Healthcare Products Regulatory Agency licence to produce human cell therapy products
The cleanroom industry has moved forward considerably since the 1960s, when the modern concept of a cleanroom was developed. It was introduced to overcome problems of contamination in facilities for hygienic operations that often had poor control and environmental systems and quite rudimentary fabric. The credit for the invention falls to the American physicist Willis Whitfield, who while working at the Sandia National Laboratories, developed the initial plans in 1962 for what we now consider to be the modern cleanroom. The design incorporated constant HEPA filtered air flow to effectively drive contaminants out of the cleanroom.
In the UK, the National Health Service, (NHS), which in the 1960s retained a large and competent engineering design capability, was largely responsible for developing the first cleanrooms for operating theatres and related facilities.
The fabric of the early cleanrooms was constructed using standard painted plaster walls with formed coving, granolithic floors with quite basic doors and architectural furniture. The early ventilation systems were equally unsophisticated and often employed relatively crude filtration systems. By today’s standards, these facilities seem quite basic but they were a considerable advance on the facilities that had been used previously.
By the end of the 1960s, it was recognised that many areas for hygienic manufacturing operations and medical procedures required considerable improvement. In the UK, the Medicines Inspectorate started to formulate guidance for the pharmaceutical sector, which culminated in the publication of the first Orange Guide in 1971; this, however, was predated by the US Food and Drug Administration’s publication of the first Good Manufacturing Guide in 1963.
While the period preceding the 1970s was fairly stagnant in terms of cleanroom design, the development of both designs and materials that then took place was extraordinary. A wide range of cleanroom construction materials was developed including self-supporting walk-on ceilings, modular units based on either Portakabin or offshore modules, disposable wall systems and the use of advanced computer modelling techniques, either in 3-D or video format.
The growing biotechnology industry was faced with quite complex issues when attempting to contain pathogens or genetically engineered organisms
At that time the growing biotechnology industry was faced with quite complex issues when attempting to contain pathogens or genetically engineered organisms. It should be remembered that at that time many vaccines were still produced with some open processing where the combination of low contamination levels and negative pressures were required. The difficulties experienced in achieving conditions that would be satisfactory to the regulators led the author to develop a contained cleanroom design that was patented and subsequently successfully used for Evans Medical’s major vaccine facility at Speke.
The speed of containment evolution during the late 1980s meant that in parallel, major developments were taking place in the design of isolator technology and the move away from open processes which meant that cleanroom design could return to a simpler format.
In some respects, investment in new cleanroom technology probably peaked in the 1980s, when the regulators and the major pharmaceutical companies drove standard to an unprecedented level. This was possible because of the high margins that the industry was able to secure.
Since then a number of factors, including the steadily reducing margins, has led to a reappraisal by many major companies of the need, or indeed desirability, of driving cleanrooms specifications and standards to ever-higher levels. It is certainly the experience of WH Partnership (WHP) that clients of all sizes, from small start-up enterprises to major international pharmaceutical companies, expect good reliable cleanroom facilities that will adequately meet the expectations of the regulatory bodies yet are value for money.
The other feature of modern cleanroom construction is the expectation by purchasers that facilities can be designed and built in extremely short timescales
The other feature of modern cleanroom construction is the expectation by purchasers that facilities can be designed and built in extremely short timescales. Because WHP recognises that the integration of the operating plant and equipment into a cleanroom is key to meeting clients’ expectations regarding time and cost, it has always considered cleanrooms to be an element of the process or manufacturing plant, instead of segregating the two elements. Hence it adopts an ‘inside out’ approach to cleanroom design rather than attempting to fit-out a separately designed cleanroom space; in fact, WHP treats the cleanroom as part of the process or the manufacturing design.
Few companies combine the full design and construction capabilities for both process plant and cleanrooms in a single organisation, which is surprising when integration of the two essential facets of clean production activities is paramount in the successful outcome of projects in controlled environment sectors. This approach worked particularly well in the case of Rosemont Pharmaceuticals (see Figure 2).
Figure 2: WHP client Rosemont Pharmaceuticals. The task was the design and build of a liquid oral solutions and suspensions manufacturing cell, incorporating micronised active pharmaceutical ingredients within a cGMP environment. The processing demands were primarily concerned with efficiently handling fine powders and liquids and the ability to create homogenous solutions, suspensions and mixtures in a cGMP environment
Today, WHP considers that the development of a process-led User Requirement Brief or Specification is essential to the successfully operating cleanroom. So often, cleanrooms are developed without this fundamental document which inevitably leads to failures in quality, purchaser disappointment and sometimes dispute. The other helpful element in the development of cleanrooms is the early involvement of the regulators, particularly when novel processes are to be carried out in the cleanrooms.
It is always a lottery trying to predict where the next significant developments might occur; however, the following are some suggestions.
As we move forward in a world that demands a reduced energy use, questions are being asked about the necessity of some of the air change rates in standards for cleanrooms and whether, by monitoring contamination levels and using more advanced controls to adjust fan speeds to match the particulate load, we can still maintain a validated system.
As we move forward in a world that demands a reduced energy use, questions are being asked about the necessity of some of the air change rates in standards for cleanrooms
One of the key elements of cleanroom design remains the wall, ceiling and floor finishes. As identified above, when the actual micro surface contours are measured, linked with the way in which partition systems are sealed to each other, there is considerable room for improvement. Various companies have used solvent welding for joints in panel systems but these are still not widely adopted. In addition, it would seem that the application of some of the new nano-particle based surface finishing systems might prove extremely helpful in improving the cleaning of finishes or even self-cleaning characteristics.
In terms of whole life costs, increasing use of isolator systems is a likely way forward, provided some of the ergonomic difficulties experienced by production staff during normal operation, at product changeovers or normal cleaning procedures can be improved.
It is surprising that the use of the sophisticated air flow patterns that obviate the need for physical barrier systems has not been more extensively developed in the pharmaceutical industry. The healthcare sector has developed some very effective air flow delivery systems that can provide high quality environmental conditions yet not require the constrictive aspects of solid barriers as used in production isolators and equipment cabinets.
In spite of the range of partitioning systems that have been developed to a very high standard of design, the most common panel systems still lack pre-designed and cost effective wall-to-wall, wall-to-ceiling and wall-to-floor components. This is an area in which WHP is actively working with suppliers to improve.
The food industry still suffers high levels of contamination in its production facilities
While the pharmaceutical, biotech and healthcare sectors have continued to advance the standards of cleanrooms, the food industry still suffers high levels of contamination in its production facilities – some of which could be significantly reduced by the appropriate application of cleanroom technology.
With the increasing use of patient specific treatments from companies, such as that offered by TC BioPharm, there will need to be a reappraisal of how cleanrooms are designed, constructed and operated. The use, for instance, of fully fitted out mobile cleanroom facilities that can be taken to health centres or hospitals to provide a treatment regime for a group of people in a specific geographical location is possibly one of the ways forward and one for which WHP is already developing conceptual designs.