A potent challenge

Highly potent active ingredients, such as hormones, cytotoxic drugs, prostaglandins, retinoids, some antibiotics and some narcotic substances, are pharmacologically active in humans at doses of 1mg or less and require special containment during processing, as defined by the occupational exposure limit (OEL) or occupational exposure band (OEB) assigned for the active drug substance.

It has been estimated that up to 50% of product OELs that are now being set by the pharmaceutical industry are at ?10µg/m3 (i.e. OEB 4 or 5).

Across the industry, there is a recognised global shortage of high containment manufacturing facilities for such active drugs. In the past, the containment approach has involved layouts of separate rooms to help prevent cross contamination, with operators wearing PPE such as air suits for their own protection. However, there are issues related to the use of PPE, which have led to a more recent drive towards 'shirt sleeve' operation within the drug manufacturing industry.

While achieving good operator protection, the use of PPE can lead to cross contamination of the working area, uncomfortable and difficult working conditions and the potential for product transfer from the containment suit.

Therefore, it has been necessary for the containment industry to advance and adapt to meet the new requirements not only for operator protection but also for product contamination as a result of the move of containment requirements from microgram to nanogram levels.

There are three key categories of containment that can be utilised:

• Downflow booths / extracted tables
• Isolators / gloveboxes
• Split butterfly valves.

The level of containment that can be ensured in each piece of equipment will vary greatly. Downflow booths typically achieve OEL's down to 20µg/m3, while split butterfly valves can provide protection generally speaking between 10µg/m3 and 1µg/m3 and isolators <1µg/m3.

There are many factors to consider when embarking on a new containment project or when upgrading current systems to meet new targets.

• Vendor experience
• Current facility design
• Process and product specifics
• Ergonomics
• Operator training and experience
• Time resource and production requirements

First, the importance of equipment vendors’ experience in solving often complex containment issues must not be overlooked.

It can be challenging to find effective containment solutions for existing equipment and facilities. The addition of a split butterfly valve as a cost-effective retrofit has proven an ideal solution where space and existing equipment constraints limit the options available, and it still meets the containment targets required for handling many APIs. The versatility of the split butterfly valve lends itself to multiple process manufacturing as a common inter-changeable interface between process steps.

It is also necessary for an isolator and downflow booths to have extra services that may not exist in current facility design. Split butterfly valves, in most cases, do not require these services.

Differing process and product specifics determine the containment performance of equipment and the selection of appropriate solutions. For the example of split butterfly valves such specifics include:

• Frequency of operations / transfers
• Quantity of solids transferred
• Size of split butterfly valve units used
• Properties of the solids handled i.e. particle size, cohesiveness.

It is also vital to consider the operators' ergonomic requirements for operating any existing equipment around any retrofit containment, or the new containment device within the facility. An ergonomic solution will prove to be more efficient and thus effective.

The operator’s knowledge of equipment is also important for an effective process. Training will ensure that the intended containment performance of a product is adhered to through correct operation. This follows through to correct maintenance and cleaning procedures ensuring the containment integrity of a product through its lifetime. Manual split butterfly valve operation and maintenance are a very simple manual procedure.

Time and financial resource, of course, can also greatly affect the decision for a containment solution. Typically, split butterfly valve projects can be turned around quicker – a very cost-effective solution when production deadlines are imminent. Isolator technology has the ability to meet more stringent OEL targets but can require more financial investment, particularly where custom designs are needed.

Penn Pharmaceutical Services, in conjunction with Powder Systems, has recently commissioned a high containment processing suite validated to OEB 4 for the small-scale manufacture of highly potent solid dose products. The suite meets the following specifications:

Class 100,000 containment manufacturing room

• negative pressure, double airlock, single-pass HVAC, safe-change EU 13 HEPA filters
• Conforms to ISO Class 8 (100,000), BS EN ISO 14644-1 (1999) & EU GMP volume IV

Closed manufacturing system

• Isolator for dispensing highly potent API
• Split butterfly valves for contained transfer of API to a Zanchetta P10 one-pot high-shear mixer/granulator/dryer.
• Further contained transfers of blend to milling & blending stages if necessary
• Contained transfer of blend to tablet press
• Validated to OEL >1<10µg/m3, OEB 4 without PPE.
• Further containment can be provided by PPE if necessary

The growth in the development of highly potent products is likely to continue. Increasingly, companies will need to out-source the manufacture of early development and clinical batches of such products to specialised providers with validated facilities and processes, to reduce the time and costs of clinical development.