Pharmaceuticals plants by design

When designing a pharmaceutical plant, regulatory requirements mean even greater attention to detail is needed than in a normal process plant. A substantial level of control must be exercised over all aspects that could impact on the quality of the product - construction materials, process conditions, and prevention of cross-contamination of products at critical stages.

Stringent regulations are in force, whether the plant is making final dosage forms or the bulk pharmaceutical chemicals (BPCs) that form the active and inactive ingredients for them. Manufacture must comply with specifications laid down in a Pharmacopoeia or similar code. Guidelines relating to BPCs have been issued by the Pharmaceutical Inspection Convention, which governs Europe, Japan and the US.

In the US, pharmaceutical manufacture is covered by the Food, Drugs and Cosmetics act: it says that 'All drugs must be produced in accordance with cGMP (current Good Manufacturing Practice)'. Hence, any bulk pharmaceutical chemicals made anywhere in the world that are destined for the US market are subject to this, and are liable for inspection by the US Food and Drug Administration (FDA). The legislation in Europe is not, as yet, so stringent, but the regulatory requirements are still substantially higher than for a conventional chemical or process plant.

Several key concepts differentiate BPC manufacture from other chemical manufacture. The regulations cover all chemicals, whether active or inactive, that are made for inclusion in a final dosage form. The principles of cGMP, as defined in the guidelines appropriate for the final market of the product, should be applied to the manufacture of BPCs. And any stage of BPC manufacture that has the potential to affect final product quality should be considered as 'critical steps', and require more attention to cGMP. These include the removal of impurities, and specific syntheses.

Design considerations

Several factors need to be reflected in the design of a BPC manufacturing plant. For example, the design of process equipment and finishes should be such that all product and process contact parts are constructed of non-corrodible compatible materials. Final product handling areas carry out finishing operations such as milling and casking, and the area and the equipment used for these purposes should be designed and manufactured to the appropriate standards to prevent product contamination.

The strict requirements must be adhered to, regardless of the scale, or whether they are ethical or over-the-counter medications, or compounds still undergoing clinical trials. A drug at the trial stage will only be required in quantities of a few kilogrammes, whereas the actives for a best-selling drug like Zantac or Aspirin are measured in tonnes. Strict adherence to cGMP is vital in either case.

A good example of a clinical trial scale plant is the recent construction of a pilot plant for Rhone-Poulenc Rorer in Dagenham by Courtaulds Engineering. This plant was designed for making clinical trials quantities and the development of processes for making them. As a part of the tendering process, Courtaulds provided six concepts for the plant, which addressed cGMP issues, incorporated deflagration features and made the best possible use of the relatively restricted site.

Courtaulds began by considering the brief and the original design proposals, and concluded that there were a number of improvements that could be made to the original design that would make it better meet the customer's requirements. The building was designed to be economical to construct by using structural steel framing to the roof, together with in situ reinforced concrete ground beams and suspended reinforced concrete ground floor slabs. A major improvement to the original design suggested by Courtaulds was that processing should take place in segregated units, each of which is connected to a cGMP-standard corridor kept under positive pressure to prevent cross-contamination.

From a safety standpoint, all processing areas have been designated as Zone 1 because of the routine handling of highly flammable solvents and reagents, and the presence of a hydrogenation unit. The location of the hydrogenation unit was crucial to the building's layout. Each segregated element in the plant was designed to withstand and relieve solvent vapour deflagration via wall and roof panels, and detonation protection was incorporated into the hydrogenation unit.

The scale of the processing modules ranges from 200 litres to 1600 litres, and each can mimic a full scale plant. Each is fully contained to prevent contamination, including the drying and packaging areas. The modules were also designed to be easily modified to reflect changing process needs.

Stringent cGMP requirements are clearly also necessary for manufacturing finished dosage forms. Sterility is crucial, as is being able to prove it. When Medevale Pharmaservices, part of the Medeva group, decided to develop its solid dose manufacturing facilities, the task was further complicated by the necessity to fit all the necessary equipment into an existing plant in Ashton-under-Lyne near Manchester.

A fast-track development was vital if production was not to be substantially disrupted. The company employed Pace Partnership as the design consultant to manage the project, and a design group was set up including Medevale employees - not just management, but also some of the staff who would be working within the area. The plan was to build in flexibility from the outset: most companies design a plant with a specific manufacturing target in mind. Here, the precise nature of the products is only known a short time in advance, so the plant was created so that adding new product capabilities can be done with plug-in systems.

'The company can still create its old formulations,' says business development manager Lesley Jewell. 'Often, when manufacturing facilities are updated, producing some of the original formulations proves impossible; this is not so here.'

Engineering for R&D

The third part of the pharmaceutical's life cycle that needs careful engineering for regulatory purposes is research and development. As this includes early clinical trials, for which the need for actives is even smaller, the regulatory authorities' requirements must still be met in the areas producing compounds to be used in human trials. SmithKline Beecham has recently substantially expanded its presence in Harlow by rationalising its R&D work from 11 sites around the south east of England. The work for the New Frontiers Science Park included the refurbishment of an office complex and the construction of two new buildings - a Science Complex and one for the Pharmaceutical Technologies department.

Again, it was clear from the outset that a flexible design was vital, as was one that provided the latest facilities and services. AMEC Design & Management was chosen to create the Science Complex and the infrastructure for the entire project. The scheme design was completed in just 12 weeks, and constructed and commissioned rapidly, within two years of design completion.

The building is H-shaped, one wing containing laboratories and the other a biotechnology pilot plant, and future expansion was catered for at the outset in the building's design. All relevant parts of the building were carefully constructed to meet the requirements of both the FDA and the Medicines Control Agency in the UK.

A project carried out by a very different contractor is the production expansion at Sandoz Nutrition in Germany. The contractor, APV, is a process plant equipment manufacturer that has expanded into carrying out project work. This is an increasingly common phenomenon (see page 37). The plant makes liquid nutraceuticals, on the borderline between pharmaceuticals and foodstuffs. These are manufactuerd to food standards which, although not quite as stringent as the general pharmaceutical requirements, still have hygiene as a major concern.

'APV's main challeneges were the fact that the end product is highly sensitive, and the process automation system needed to allow the opportunity for extension,' says Frank Ziemen, APV process engineer.

Eight APV plants supplied equipment for the installation, ranging from mixers and homogenisers to automation and control.

This work by APV marks part of a growing trend for equipment manufacturers to expand into project management rather than just supplying machinery. As the market for plant becomes ever more competitive, we will see growing numbers of equipment manufacturers carrying out major installations in this way, in competition with the traditional contractors.

Dr Sarah Houlton is Managing Editor of PE's sister title Manufacturing Chemist