By Michelle Frisch
Powder Systems Limited
An obvious trend for increasing containment requirements

As drug development and new chemical entities become ever more potent, we see a clear and rising trend for safety measures when these essential yet dangerous products are handled. Requirements for robust contained facilities are continually increasing: 10 years ago, potent compound facilities were typically being designed to achieve containment levels of <10micrograms/m3, many of these facilities remain in good working order, yet are not capable of meeting today’s stringent requirements. It’s not just the ipod that has gone nano – a large portion of pharmaceutical facilities are now being forced to achieve nanogram level containment, be it for new products in the pipeline, or anticipation of such products in the immediate or near future. We are also seeing that the issue of containment and operator exposure is becoming an increasingly important area in formulation and secondary manufacturing facilities, whereas previously containment was primarily an issue for R&D and API production. As capital expenditure is scrutinized by even the most lucrative pharmaceutical companies, building a new facility every 5 years is not a feasible approach, this is where retrofitting or upgrading containment to an existing facility often becomes an attractive option.
Why retro fit?

As with many key issues in industry these days, cash is a key driver. Upgrading an existing facility is often more cost effective than building an entirely new facility and kitting it out with the latest in contained process equipment. Not to mention the time and resource involved in getting a new facility validated by the FDA. By retrofitting containment to existing process equipment, the core process remains unchanged, therefore the processes do not need to be re-validated. The time consideration is also favourable when retrofitting rather than purchasing new equipment – as the lead time for the manufacture of complex machinery, such as a new contained tablet press, is considerably longer than for an isolator to be retrofitted to an existing tablet press. Downtime of the facility can also be kept to a minimum as the installation and commissioning of a retrofitted isolator can take place in as little as two weeks, if timed correctly this can have little or no impact on production schedules and targets.

Key considerations

Now it would appear that retrofitting containment would be the ideal solution, and this can be the case, however there are some key considerations that need to be taken very seriously if your project is to be successful, both in the short and long term.

Consider the entire process

First and foremost, it is highly recommended to consider the entire process, upstream and downstream, to ensure containment throughout. This will avoid unnecessary reworking at a later date. For example, when attempting to contain a charging operation, it makes sense to consider also the discharging later in the process at the same time, even if this is not a current requirement, it is likely to become a requirement in the future. When upgrading an existing facility and established process that was designed when containment was not an issue, it is important to approach the project with an open mind as there are often compromises that can be made which will simplify containment.
Ergonomics is the key to operator buy in

Ergonomic design can be the making of a successful project. If an operation is simple to carry out within an isolator then the task of convincing the operators that this is a good move will be considerably easier. It may sound obvious, but you should consider how the operation will actually be carried out within the isolator. For example weights feel much heavier at an arms length, so simple ideas like placing a shelf to hold the weight of a machine whilst stripping it down for cleaning can make a remarkable difference to the ease of operation.
Mock ups can identify issues at an early stage

A sure recipe for success is to perform a design study, surveying the existing plant, and building a mock up of the proposed containment system. This exercise is invaluable in ironing out ergonomic issues at the beginning of the project – before it becomes time consuming and costly to make changes. This exercise also provides the perfect opportunity to gain operator buy in, if the actual operators perform the ergonomic testing, they will feel they are a part of the project and may contribute towards the design – providing valued input to the project. This will go a long way towards them embracing the technology when it is introduced onsite and they may even act as an internal ambassador for the new equipment.
Flexible thinking

When attempting to retrofit containment to larger production scale units, then it is often feasible to consider flexible barrier isolation techniques. Hybrid units with rigid frames and flexible windows can be the perfect solution where a large reach is required to access rear areas, especially if the access to the machine is restricted.
Modifying process equipment

When applying barrier isolator technology to an existing piece of process equipment it is not always necessary to contain the entire piece of equipment. With many machines, such as granulators and mills, the powder facing parts of the equipment can be placed within the isolator, with other parts, such as drives and motors, remaining external. This has more than one advantage, firstly the isolator can benefit from a more compact design as there is no need to house the entire machine. Secondly, cleaning of the inside of the isolator is easier as there are less potential product trap areas within the isolator. And finally, maintenance is easier as access to motors is not restricted.
Addressing cross contamination

Avoiding cross contamination, and ensuring cleanability of equipment, can be a critical factor in facility design, especially in multi-product facilities. Careful attention must be paid to details such as, drainage points and wash in place systems & surface finishes. You have to define whether a wash in place (WIP) or clean in place (CIP) system is required. The main difference between the two is that with CIP you have to be able to validate the repeatability of cleanliness. This can be achieved by additional treatments such as passivation and engineered design such as self draining bases. A riboflavin test, during FAT or SAT, to prove the system efficacy is essential for both WIP and CIP systems.

Some key additional equipment should be incorporated such as a flexible wash hoses & rotary sprayballs. These are recommended to ensure that all areas of the equipment can be thoroughly washed down. Often time is of the essence with multi-product facilities – if this is the case, then WIP and CIP systems can be provided with manifolds which allow feed of hot air to aid drying resulting in rapid product turnaround.

Existing facility constraints

So far we have been considering integrating isolators into existing facilities. While barrier isolation is a very effective method of protecting operators from potent and harmful products, with existing facilities there are often physical constraints, such as pipework or limited headroom, making it virtually impossible to fit an isolator into existing space. If this is the case then it could be that the implementation of split butterfly valves, to transfer powder from one part of a process to the next, is a suitable solution. Split butterfly valves can be fitted to equipment where space is at a premium, and are a flexible option for containing various product transfers. Recent advances in split valve technology has seen exposure levels can be reduced to <1microgram/m3, and as the installation of such valves is relatively simple, provides a robust containment solution for minimum disruption.

Act wisely

As new drugs continue to increase in potency, so do the safety requirements for those scientists and operators that discover and produce the medicines that we have become so reliant upon. We have seen that retrofitting containment can provide a cost effective solution when upgrading facilities to handle more potent products. The benefits can be great both in terms of time required for implementation, from inception to completion, and capital investment required. However it important to treat each project individually, carry out a front end design study if at all possible, and carefully consider each of the items we have discussed. At the end of the day, operator safety is the key aim, if retrofitting is possible then great, however, as we mentioned earlier, it is important to have an open mind – equipment manufacturers are gaining in experience in devising innovative solutions for these ever more difficult challenges – so be sure to consult those with the experience in these issues.

About the author:

Michelle Frisch has been working with the pharmaceutical industry for over 10 years, specializing in containment technologies and innovation solutions design. She is currently Manager of the US Technical Containment Systems Division of Powder Systems Limited. Michelle is a member of the American Glovebox Society and holds a position on the Standards Committee. She is also a member of the American Institute of Chemical Engineers.