Containment issues are becoming an increasingly important aspect of solid dose drug production. Active pharmaceutical ingredients (APIs) are becoming progressively more effective and, at the same time, more than 50% of all new chemical entities (NCEs) are being classified as potent (OEL <10µg/m3).
In addition, the health and protection of operators all over the world is being put under an increasingly intense spotlight. During production, particular attention must be paid to both preventing operators from exposure to the drug being processed and eliminating cross-contamination. In recent years, the focus of operator protection has shifted from cumbersome personal protection equipment (PPE) to contained solutions to avoid operator and product contact.
PPE protects only the operator. The hazardous substance being processed is not contained, which means that the associated problems are exacerbated: changing filters and cleaning rooms and equipment inside and out become major containment issues.
Additionally, depending on the PPE system used, the levels of protection are limited. For systems taking air from a room using a filter system, the best filters (P3 according to EN 149) offer NPFs (Nominal Protection Factors) of 30. This means that if the dust concentration in a room is 3mg/m3 (typical for open production), at best the concentration inside the system will be 100µg/m3. Furthermore, the lifetime of the filter element is limited because of the high dust loading.
Working conditions inside an air-suit are hot, humid with poor visibility and limited movement, which results in low levels of operator efficiency and the need to take frequent breaks
The situation is slightly different when air-fed systems are used; they offer better levels of protection, but there are still some areas of concern. The performance of these systems is very operator-dependent and the working conditions inside an air-suit are unpleasant: hot, humid with poor visibility and limited movement, which results in low levels of operator efficiency and the need to take frequent breaks, reducing efficiency further. It is also important to notice the hidden costs associated with such systems (suit and filter lifetimes are limited, there are costs related to clean air supply and a requirement for extra changing and storage areas).
Yet PPE-free production is a widely proven technology. GEA Pharma Systems has already implemented a number of successful solutions using a combination of the containment technologies that it has in-house, not just for the main processing operations, but also for all the transfer steps between the unit operations – for cleaning in place or for contained offline cleaning, and for sampling and in-process control.
In fact, there is no longer a need for any drug production system to use personal protective equipment. But whether the pharmaceutical industry is ready to adopt this paradigm shift in containment is another matter. A key requirement to operate such a system is a higher standard of operator training and a better maintenance regime. It requires use of engineering solutions and equipment design solutions to achieve operator protection, as opposed to wearing PPE, which is a relatively easy thing for companies to train their staff to use. It has a higher technical requirement, so whereas some customers and markets take to that very easily, others find it something of a challenge.
Drivers and benefits
There are a number of drivers behind this switch to PPE-free manufacturing. First is the ongoing and increasing focus on operator safety; European and American customers have had this in place for many years. However, some people miss the fact that every country in the world – including those that are sometimes considered to be less well developed – are all under increasing pressure from governments and from their national health and safety executives to improve the working conditions of their personnel – both in general and particularly in the pharmaceutical industry, with regard to operators being exposed to increasingly potent drugs.
From a regulatory perspective, there is a relentless push for more stringent guidance with geographically diverse timescales: Europe and North America implemented legislation 15 years ago, for example, and in China, under the aegis of a so-called ‘increased GMP standard’, there is a massive drive for increased operator safety.
There are cost penalties to implementing a containment solution, but there are also cost benefits. By keeping the problem inside the system, the room and the equipment outside is not contaminated. And when it comes to cleaning the line – for product changeover, for example, or to start a new batch – the amount of downtime or labour required to clean the room and/or the outside of the equipment is dramatically reduced. This gives a more cost-effective operability.
Now customers are deciding to run potent facilities without having airlocks on every single room
Another direct benefit is that, in the past, many customers would buy an intermediate bulk container (IBC) washing system – to not only wash the inside of the container, but also the outside. Now, with a contained system, the outside of the container does not become contaminated, as it is not a product contact surface and, as such, a much simpler – and therefore much cheaper – IBC washing system can be operated. And, by keeping the product inside the system, different products can be manufactured in parallel without the risk of cross-contamination.
In the past, companies would be able to process only one product at a time, unless they had a complex setup involving airlocks, cleanrooms and isolators to avoid the risk of product loss or contamination. Now customers are deciding to run potent facilities without having airlocks on every single room. That is not only a big saving in costs, it is also a saving on footprint and, subsequently, running costs: fewer rooms, less HVAC, less expense. And they are doing that purely on the basis that with a good containment system, the product remains inside the equipment and does not enter the room; there is no risk of exposure or contamination.
The single-supplier advantage
The key to effective containment is identifying the most appropriate solution based on a thorough understanding of containment risk analysis. Keeping the real operating conditions of the final installation in mind (the same level of containment may not be required throughout the entire line), it is essential to determine what level of containment is required where, optimising the manufacturing process and making it efficient, safe and cost-effective.
Even for experienced people, navigating the maze of available hardware components and the huge variety of containment solutions has made it difficult to select the most appropriate equipment for the specified task: suppliers of various hardware components have developed a huge variety of containment solutions, making it difficult to decide on the optimal solution.
GEA Pharma Systems has already implemented a number of successful solutions using a combination of the containment technologies that it has in-house
Although there is a vast array of available equipment and machinery from a number of suppliers, a key benefit of working with GEA is that it can supply an entire, completely integrated, containment system, from raw materials handling right through to tableting. One of the challenges with any containment system is the integration of the different pieces of process equipment. It is not just about having split valves, it is also about making sure that the materials handling system integrates with the granulation equipment and with the compression equipment. GEA offers group-wide technical solutions that can be integrated into complete lines.
This is becoming increasingly important with the growth in oncology and hormonal products, especially in batch direct compression systems (in which the ingredients are blended in an IBC and fed directly into the tablet press).
The future of containment
The past 20 years have seen a significant increase in the need for contained handling and processing in the pharma industry, driven by the development of more potent APIs and a focus on health and safety by the regulatory authorities.
The message has never been clearer: it is the first duty of the employer to protect the health of their staff
Established standards and practices in Western countries are now being adopted in emerging geographies as mandatory procedures migrate from using PPE to maintain operator safety to practising containment at source.
The message has never been clearer: it is the first duty of the employer to protect the health of their staff. And PPE has been found to be inadequate during modern pharmaceutical drug production.
In addition, it is becoming increasingly apparent to manufacturers that the implementation of seamless containment solutions offers considerable housekeeping benefits, such as:
- faster changeover times owing to reduced (room) cleaning
- significantly decreased cross-contamination risks
- substantial savings (e.g. air filters, air suits, contaminated cleaning fluid).
Looking further ahead, if PPE-free working environments are already with us, what does the future hold for containment? Just a few years ago, establishing how contained pharmaceutical manufacturing could be used was very much the market driver. Today the emphasis is on applying science to evaluating operator risk and establishing how much containment is actually needed for a particular process or application.
It is very easy to over specify the containment requirement for a product. When that happens, the equipment is not only more expensive to buy, but also more difficult to operate, maintain and clean. And that does not benefit anybody.
The key to effective containment is identifying the most appropriate solution based on a thorough understanding of containment risk analysis
Case study: Direct compression of hormonal tablets
Wishing to maximise the solid dosage production of a highly potent hormonal product, a leading drug manufacturer tasked GEA Pharma Systems with significantly increasing its output, providing a safer and more efficient factory environment and introducing new systems that would replace the existing isolator-based process.
The challenge for GEA was to use its product flow and containment expertise to remove as much isolator-based processing as possible, making the production flow more efficient while maintaining the high levels of containment and operator safety required. Another key factor was maintaining blend homogeneity. GEA first demonstrated a patented high containment system, the MODUL S rotary tablet press with a Wash-off-Line (WOL) Exchangeable Compression Module (ECM). It also demonstrated the use of multi-tip tooling: using two tips per punch (station) doubled the tablet press output. A specially designed feeder and dedicated software ensure optimal output.
GEA then demonstrated its ability to blend successfully the low levels of API with poor-flowing excipients using its blending Prism technology, an effective aid to the bin-blending process. The new system was fast-tracked; the preliminary details were agreed within four months and the equipment delivered less than a year after contract signing. Removing much of the isolator-based processing and expanding into new factory space will enable a significant increase in both batch size and yield and will improve the working environment.