Reliability and efficiency are two major hurdles to overcome in pharmaceutical containment, but can be overcome through proper planning. This must result in robust, ergonomic isolator design, taking into account the need to modify process equipment, powder handling requirements, explosion risk, cleaning regimes, glove material choice and sampling procedures.
When designing isolators it is important to evaluate glove material to assess glove permeability for all materials being handled
Reliable and efficient high containment continues to be a challenge for the pharma industry. Maurice Pitcher, ceo of Powder Systems Ltd (PSL), a specialist in pharmaceutical containment, looks at the main hurdles and outlines some key considerations.
With current technology, operator exposure levels (OELs) of 10–50 nanograms/m³ 8hr TWA can be readily achieved and should not present an unreliable outcome. However, some of the key failure modes observed over many years include:
Let us consider the main influences providing more positive and controlled outcomes.
The number one priority is operator safety and drug quality. When developing drugs, the use of novel materials means that the risks are not fully understood at the early stages. I remember as a laboratory technician getting the ‘flu’ when working on a single cell protein; this turned out to be a universal allergic reaction and nobody had been aware of this at the early development stage.
Companies have to be ultra conservative until they have established sufficient data for the product. It is not untypical for a research level of nanogram/m³ to be relaxed to 1µg by the production stage.
A common method to establish OEL performance is to use a placebo, such as a micronised lactose with a d50 at approximately 20µm (see graph), which accredited laboratories can detect at 2ng. For more established products, it is clearly advisable to develop test methods and carry out checking with routine follow-ups for that specific product.
Micronised lactose size distribution commonly used to establish OEL performance
SMEPAC (standardised measurement of equipment particulate airborne concentration) is a useful guideline to follow when measuring OEL. It takes into account background prior to testing and potential weak points around the equipment in addition to passing traffic. It will also allow comparisons of performance.
There has been a trend in recent years to have bands of OEL for facility performance. When validating, we need to ensure that we test to the lower level. A regular method is to simulate three operations over one hour, for example, and utilise this result in a Total Weighted Average (TWA) consideration.
Utilising an additional 10:1 safety factor, for example 0.1µg/m³ rather than 1µg/m³, is questionable. There is already a considerable safety factor built into the initial OEL objective and this additional factor has been used due to unreliable system design. This is not a scientific approach, as it would suggest a lack of knowledge and understanding resulting in unnecessary cost and complication.
So where does the unreliability come from? When buying a reactor, dryer, granulator, mill system or filling machine, you expect it to work. A containment provider has truly to understand all relevant manufacturing processes to ensure practical and safe solutions. If you are not confident in the containment provider’s understanding, you will have problems.
Performance levels should also have guarantees otherwise there is no confidence in outcomes.
Examples of problems with process safety include an instance in the past where one engineer wished to charge a strong oxidising agent through the same glovebox system as organics to a vessel. One would hope this would eventually be recognised as an unscheduled reaction in the glovebox.
Furthermore, several dust explosions have been observed in dispensaries where the difference of a sealed enclosure as opposed to an open downflow booth has not been recognised.
Figure 1: A high containment filtration and drying isolator (FilterBox) mock-up
Your containment provider should be able to assess with you the following:
Figure 2: A GFD FilterBox 3D model showing the drive outside the acrylic isolator
Figure 3: Multi-purpose dispensing and sampling isolator with drum hoist system
Figure 4: A 0.6m² filter dryer with minimum gap design allowing reflux cleaning
If unfamiliar with the practice of high containment, it is worth making some benchmark visits to other manufacturers. It is a good investment to spend time with your supplier early in the planning stage and review the design alongside a draft User Requirement Statement (URS). This will help to avoid surprises further down the line and ultimately increase the success of your project.