Market strategy backs one-pot granulation

For more than 30 years, fluid bed technology ruled the roost in the drying of solid dose products. However, one-pot processing may be about to make its mark

Despite its obvious attractions, one-pot drying and granulation has so far failed to live up to its promise in terms of market share. But the booming generics sector and growing preference for the research-based industry to outsource mean that one-pot technology may at last make its mark

For more than three decades, fluid bed technology has reigned supreme in the drying of solid dose pharmaceuticals, with the market dominated by two major players, Glatt and Niro-Aeromatic. In combination with a separate granulator, it is regarded as a highly efficient system.

As with many long-established processing methods, however, the fluid bed has its shortcomings, with filtering of large volumes of air, regulation of air flow, product loading and containment of powder in the process room all listed by users as points of concern.

The risk of explosion — particularly with solvent-based preparations — is considerable, necessitating extensive and expensive safeguards. But so pre-eminent is fluid bed's market position that many companies have chosen to work around these limitations rather than seek an alternative.

There are nonetheless situations in which fluid bed technology simply will not do and it was one such set of circumstances which, 17 years ago, gave rise to an apparently promising contender ; the one-pot system. Italian pharmaceutical producer Menarini needed to produce a highly active, hormone-based compound at its plant in the city of Florence but the explosion risk of a fluid bed system in such a densely-populated area was considered too high. Local manufacturer Zanchetta, now a part of Romaco, provided the solution in the form of the first one-pot system, capable of handling drying and granulation phases in a single, contained vessel.

Simplified GMP

Zanchetta has subsequently installed over 200 units and has been joined in the market by major players, including Collette and Bohle. The advantages these manufacturers claim for their systems include simplified GMP and regulatory compliance, total containment, easier process automation with lower manpower requirements, higher product yield and quality, and eliminating the potential for environmental pollution.

Despite these advantages, however, the one-pot does not appear to have fulfilled its promise in terms of market share. A recent survey of manufacturers using fluid bed systems can perhaps show why. Questioned about the perceived barriers to changing or updating their technology, 40% of respondents cited re-evaluation of processes as the main obstacle, 22% cited the problems of optimisation and scale-up on new technology and 19% said that operator re-training was the major concern.

Drying and granulation are certainly among the most critical operations in pharmaceutical production, with the need to produce a high-quality, homogenous granulate paramount. There are further issues at play here, however, including in many cases the manufacturer's desire to protect his intellectual property, particularly for patented products.

Product Licences and patents are therefore frequently drafted very tightly, even to the extent of specifying the equipment used in the process. This is certainly a means of protecting market position but there is no doubt that it does hinder flexibility and advancement.

However, changes in the structure and modus operandi of the pharmaceutical sector are now creating new opportunities for the one-pot manufacturers.

Pressure on healthcare budgets from governments around the world has given impetus to the generics sector and with patents on 15 of the world's top drugs expiring in the next four years, it is a boom which looks set to continue.

Already, generics manufacturers will have identified the drugs they plan to manufacture and will be looking at formulations, product licences and production methods.

There is also an increasing preference among research-based pharmaceutical companies to concentrate on their core competencies of product development and marketing, with the result that manufacturing is more likely to be outsourced.

Generics and contract manufacturers face similar challenges in terms of lower margins — the unit cost of a generic product averages less than one-fifth that of its patented predecessor — and the need to offer a fast and flexible response if market share is to be maximised.

Flexible utilisation

Lower margins mean that manufacturers need to look to economical production methods to maintain profit levels. There are a number of potential routes here, including high and flexible equipment utilisation, faster processing methods, higher yields and lower operational costs.

One-pot processing can justly claim to offer significant advantages in each of these respects. Although, at 90%, typical utilisation of fluid beds is high, it is significant that most systems are used to produce large batch volumes of a single product. In the fast-moving generics and contract environment, it is likely that processing equipment will be used for a variety of different products and must therefore have the flexibility to cater for a variety of processes.

One-pot systems score well in terms of flexibility: in basic executions they can handle both water and solvent-based formulations, products which are sensitive to air, heat or moisture, and are suitable for melt granulation processes and one-step effervescents production. With the addition of a tilting bowl — now offered by the leading manufacturers in the field — one-pot systems can also compete with fluid beds in pelletisation and the processing of products which are susceptible to mechanical stress.

Discharge and cleaning

Another aspect of machine utilisation that is increasingly scrutinised is that of overall batch times, from loading product at the start of one batch right through processing, discharge and cleaning, round to loading raw materials for the next batch.

One pharmaceutical industry representative recently said, 'If you look at some of our pharmaceutical plants, our core competency is equipment changeover and cleaning. We spend more time doing that than actually making the product.'

While fluid bed manufacturers can justifiably claim that their actual batch processing times are faster than that of a one-pot system, post-production cleaning is a major problem. Over half the fluid bed users surveyed reported that cleaning times were between five and 12 hours, compared with the three hours claimed by one-pot manufacturers.

Because the one-pot is a single, contained system, it is easier to clean than a granulation suite incorporating granulator, wet mill, fluid bed dryer and dry mill.

Most one-pot systems incorporate a fully automated CIP system, as opposed to fluid bed systems, which feature only partial systems, leaving one of the most critical aspects — that of cleaning filters — as a manual process.

Batch and subsequent cleaning times naturally vary from installation to installation but one-pot producers argue that ease of cleaning makes their batch-to-batch times quicker than that of fluid bed installations by a margin of around 25%. And with the addition of options such as Collette's microwave drying or Zanchetta's gas stripping, drying times can be cut further, albeit at a cost.

This higher level of equipment availability also facilitates higher product yield, as does the fact that as a contained process, one-pot manufacturing is less susceptible to product loss. Yields for one-pot systems are typically estimated to be greater than 99%, compared to 98% in fluid bed production. It is a small difference but given the value of some pharmaceutical actives, it can be significant.

It is difficult to estimate the amount of pharmaceutical production lost through spoiled batches, as any mention of the subject seems to be proscribed. However, it is beyond doubt that they occur and one-pot manufacturers believe that their systems offer the solution.

The argument goes that the entire process takes place in an atmosphere-controlled vessel, making it far easier to automate. Thus, critical process phases, such as the all-important granulation end-point, can be precisely calculated, with the system programmed to respond accordingly, because all variables are known and controlled.

Levels of reproducibility

According to the one-pot lobby, full process automation is far easier to achieve with their systems and the resulting elimination of atmospheric variability can significantly cut the level of product loss attributable to spoiled batches. Automation also contributes to high and consistent levels of reproducibility from batch to batch.

In terms of operating costs, the one-pot is the clear winner. Energy consumption is significantly lower, while the floorspace requirement is typically just half that of a fluid bed suite of comparable output. This has spin-off benefits, such as lower costs for fitting out premises and lower air filtration costs because the entire process is contained in a single vessel. The aspect of containment is particularly significant in processes involving solvents, as their recovery from a contained vacuum vessel is far easier than from the large volumes of air used in the fluid bed system. The higher levels of automation possible with a one-pot system also offer cost savings, thanks to a reduced manpower requirement.

So the case for the one-pot appears strong but is it strong enough? The answer depends on a number of factors. Fluid bed installations excel in the production of high volumes of a single product — particularly those which are water-based and non-toxic. If this is the case, then the inconvenience of switching to a new technology and re-writing product licences may not be warranted.

If, on the other hand, containment, safety, flexible and economical production are high on the company's list of priorities, the attractions of the one-pot appear compelling. It may well be worth re-visiting those product licences.