High Containment Milling of Potent Compounds in the Pharmaceutical Industry
George TunnicliffePharmaceutical Business Manager, Kemutec Group Ltd
Martin ThomsonTechnical Sales Manager, Kemutec Group Ltd
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Introduction
With the trend towards pharmaceutical products of higher toxicity requiring greater standards of containment, the protection of mill systems against the consequences of a powder explosion are of ever greater importance.
The selection of explosion protection method is often made at a late stage in the mill system design when many other parameters have already been fixed, however the method of protecting the system from an explosion can be highly interactive with other process requirements.
In order to achieve an optimum overall design for the system it is therefore necessary to have a good understanding of the relative merits of the various methods of explosion protection and to consider these at in early stage in the design process.
The purpose of this paper is to examine practical, cost effective solutions to a variety of mill applications where the need is to provide total protection against the risk of a powder explosion whilst maintaining effective operational control over product emissions.
Why Containment?
The surge in demand for containment in the pharmaceutical industry, and indeed in other industries, is a direct reflection of the increased potency of modern drugs and the demands of ever more stringent legislation. This has challenged the pharmaceutical companies and, in turn, their equipment manufacturers to meet the criteria. Here we consider the implications for manufacturers of size reduction equipment where impact, air-flow, temperature, high speed rotating components, bearings and seals are all design considerations in addition to the hazards of the product being processed.
What are the issues?
As pharmaceutical compounds become more potent, acceptable Operator Exposure Levels (OEL’s) are reduced. The trend towards finer Particle Size Distributions (PSD's) makes effective containment more difficult. Finer PSD’s also make products more of an explosion risk. In addition, legislation is getting tougher - the ATEX regulations came into effect on 1st July 2003 in the European Union. Despite this, there are still the commercial pressures to ensure that equipment costs are kept under control whilst meeting these higher standards.
Factors influencing the containment solution
The key factors influencing the containment solution for any process include; the toxicity and associated OEL level’s of the materials to be handled, their PSD's both before and after processing, the pressure at which the process takes place, any change in product characteristics after processing and, the explosion risk characteristics of the product.
Milling systems pose all of these problems and particularly at the system’s end points i.e. the material in-feed and discharge points and also at the mill’s air/gas intake & exhaust vent.
Handling potentially explosive products
The provision of explosion protection for a milling operation can significantly add to the cost, size & complexity of the system. Poor selection of explosion protection method will waste money and compromise the system’s operational efficiency. It is important to have a good understanding of the relative merits of explosion protection methods in relation to the process requirements.
The four recognised methods of dealing with the explosion risk in a milling system are: Venting, Suppression, Inerting and Containment. Venting is clearly not an option when dealing with potent, toxic or otherwise hazardous products. The last thing you want to do is to spread such materials far and wide aided and abetted by an explosive force!
Although the principle of suppression does not compromise the containment requirements of a system, it is not widely used in the pharmaceutical industry. This is due mainly to the amount of clean up required in the system after a suppressant discharge and because it involves the introduction of materials that may be detrimental to the product which may have a considerably high value.
The two methods preferred by the pharmaceutical industry are Inerting and Containment.
Inerting Systems
Inerting systems use an inert gas such as nitrogen or argon to reduce the oxygen level to below the limit that will support combustion. Their main advantages are that they do completely eliminate the possibility of an explosion, the system can be sited anywhere and they are ideal for low Minimum Ignition Energy (MIE) materials. Disadvantages include increased system cost, ongoing cost of the inerting gas and the need to protect operatives against hazards such as asphyxiation or “cryo burns” if the gas is generated from liquid. Safe venting of the inert gas must also be catered for which may be problematic dependant upon site layout etc.
Fig. 1: Typical Inerted high impact milling system
Containment Systems
Containment systems are constructed to contain the maximum pressure rise during an explosion. Such systems can be sited anywhere, they do not compromise the containment OEL's in the event of an explosion and there are negligible maintenance requirements. On the other hand, there is the higher initial cost of manufacture and explosions can take place, which may not be suited for use with sensitive, low MIE materials.
Fig. 2: Typical Explosion Containment high impact milling system
Are there alternative designs?
At Kemutec we have asked ourselves, "Can we utilise the ‘best bits’ from the standard traditional methods? Can we produce compact mill designs to aid containment issues – e.g. Use of gloveboxes? Does this need to incur additional expense?
One solution is the Closed Loop Milling System. Closed loop systems can be based upon the containment principle. They are much more compact and cheaper than traditional containment designs. The mill process gas is re-circulated around the system, which eliminates the need for filters, slam shut valves, etc.These systems offer easier cleaning with less chance of cross contamination.
Fig. 3: Typical Closed Loop high impact milling system
Photo. 4: Conventional Containment system with filters
Photo 5: Closed Loop system without filtration.
Caption under both photos: Closed Loop systems enables size of package to go from this (photo 4) to this (photo 5).
Fig. 6: Comparison between Vented, Containment with Filtration and Closed Loop mill assemblies, shown to same scale
Closed loop Mill systems have many advantages but they may still not be suitable if the product has a low MIE and is prone to dust explosions. We need to consider a system to cater for this class of materials hence the development of the Inert/Closed Loop Hybrid System. This offers many of the advantages of the Closed Loop method, (compactness, clean-ability, etc.) with the additional advantages that the inert processing atmosphere enables its use with even the most sensitive materials. They do require the use of filtration, but because you are only venting ‘top up’ volumes of gas, these can be small “throw away” units. Also they do not require construction to withstand pressure shock containment.
Fig.7: Hybrid Inerted-Closed loop high impact milling system
Gloveboxes
For the ultimate in containment, milling systems can be enclosed in "gloveboxes". Closed Loop & Inerted Closed Loop systems are ideally suited for use within Gloveboxes.
Their compact design requires a smaller enclosure with fewer penetrations through the walls. Where required, the gas flow through the enclosure can be chilled to limit the temperature rise of the mill. Our experience confirms that system mock-ups benefiting from operator input at an early stage of the design process allow confirmation of the ergonomics. This saves potential costly rework of equipment and manufacturing delays.
Photo. 8: Mocked up Glove box
Photo. 9: Completed Glove box
Key Factors
Milling Equipment - Impact Mills are suitable for average PSD's of 30 microns.
OEL Levels - Gloveboxes to suit OEL's sub 10mg/m3
MIE Value - Nitrogen inerting to suit MIE's of 3mJ
CIP - Glovebox allows access to mill with wash lance
Product Value - One final (not insignificant) point – The value of the product (which can be $100,000 per gram and higher) can also impact upon the design criteria!
Summary
Explosion protection is an integral part of the overall containment philosophy as issues such as; material characteristics, site conditions and operational requirements will all influence the choice of explosion protection method. For this reason, the method of explosion protection should be considered in the initial stages of the system design process.
Because of their compact design, closed loop mill systems can reduce overall cost and space requirements particularly when used in conjunction with a glove box while maintaining the containment principle.
Low MIE products can be treated effectively with the use of a hybrid Closed Loop-Inerted operation whilst retaining most of the benefits of closed loop containment operation.
For further information, George Tunnicliffe and Martin Thomson can be contacted at Kemutec Group Ltd on +44(0)1625 412000 and by email on and respectively.
About the Authors
George Tunnicliffe joined Kemutec in 1979 as Chief Design Engineer and in the early eighties he was seconded to assist in the start up of Kemutec Inc (now Kemutec Group Inc), the group’s sister company in the USA.
Following this he was appointed Group Technical Manager working on a variety of applications including cryogenic milling techniques, granulation processes and centrifugal sieves.
In his current role as Business Manager for the Pharmaceutical and Packages Division he now has responsibility for all activities within the division including sales, product development, test centre operations and systems engineering.
George holds a BSc in Mechanical Engineering and sits on the technical sub committee of the UK Solids Handling and Processing Association, which comprises around 100 UK organisations involved in the field of powder processing & handling.
Martin Thomson is a Graduate Engineer with an MSc in Bulk Powder Materials Handling from Glasgow Caledonian University, Scotland. He was presented with the Newcomer to Bulk Materials Handling Award, by the Solids Handling Journal in 1992 for original work carried out on behalf of BP Chemicals.
Martin joined Kemutec Group in 1993 and has spent the last 10 years working closely with pharmaceutical companies around the world, gaining hands on experience in solving their powder processing requirements. His early positions as Commissioning Engineer, Site Manager and his current role as Technical Sales Manager have allowed him the opportunity to witness at first hand the typical problems associated with the milling of pharmaceutical powders.