Safe handling of bulk APIs

Carlisle Life Sciences Europe (CLS) recently completed the testing of five high containment powder pack-off systems manufactured specifically for a client in Ireland.

The equipment is designed to provide safe, reliable levels of operator safety, while packing-off IBCs containing active pharmaceutical ingredients (APIs) into accurately weighed 50kg drums. The containment performance objectives for this project reflect the acute hazards that are involved in handling these types of potent material. The compound has an Operator Exposure Limit (OEL) rating of only 1microgram/m³ of air. To put that into perspective, an average grain of granular sugar weighs approximately 100 micrograms/m³. With this operation, therefore, the maximum permitted dust exposure to the operator is a mere 1/100th of a grain of sugar in 1m³ of air. Prior to delivery, stringent testing of the equipment was carried out to prove scientifically that the units will be safe in operation and meet the required OEL. CLS has a well developed test protocol that provides accurate data on these key factors: • Airborne dust-escape during typical drum filling operations • Surface contamination levels of drums exiting the isolator • Chamber inertion with nitrogen prior to powder transfer • Clean down performance of the built-in CIP system. Testing of bulk powder-handling systems, without having the bulk process on hand, has demanded a certain amount of ingenuity and hardware development, including the creation of a purpose-built cleanroom around the pack-off system. The test isolator was located in the cleanroom, which is capable of being pressurised to 25pa. Powder feed, to simulate the IBC discharge, was set up using a sealed overhead hopper with a PIAB vacuum transfer system. To avoid contamination of the workshop the test powder was vacuumed from an anteroom maintained under negative pressure. Fig. 1 shows a cross-sectional layout of the set-up. To test isolators to microgram or nanogram containment levels, OELs are usually measured over an eight hour work shift, which forms the basis for HSE legislation. In this instance, we are interested in evaluating the containment performance only during the peak periods of dust generation, specifically for drum-filling. When testing isolators to extremely low levels it is important to remember that conventional occupational hygiene dust monitoring levels (using gravimetric analysis of dust build-up on the sampling filter) will not be accurate at these very low levels of contamination. Over the past five years CLS has developed a paracetamol/HPLC assay method, which uses micronised paracetamol powder as the test dust. Paracetamol can be traced to almost molecular levels using high-performance liquid chromatography and this analytical technique works for both airborne dust sampling and for surface contamination, simply by using sterile throat swabs.

Selecting the correct device The starting point is selecting the correct containment device and CLS has developed the "Pyramid Chart", which permits quick and easy evaluation of the key factors that drive the need for isolation technology. These are the Exposure Potential – i.e. how much dust the operator will generate carrying out the specific task in question, and using the specific material for the process; and the Hazard associated with the compounds to be handled – i.e. its OEL. The chart (Figs. 2-4) will push the decision into one of the five industry-accepted containment strategies. In this example, the quantities of material being handled give an Exposure Potential level of EP3. The OEL of the material (1.0microgram) is in Hazard Band D (Fig. 3) giving a recommended level at "Containment Strategy 4". Containment Strategy 4 (Fig. 4) considers barrier isolation/glove box containment, where the internal surfaces of the isolator are protected from contamination by a "direct transfer connection" – in this case a continuous liner device. The isolator design developed by CLS was evaluated for ergonomic acceptance early on in the contract stage, when a full-scale wooden mock-up was created for operator evaluation. Mock-up review is essential to ensure that the operator can actually complete the task when working via glove ports. The isolator layout was based upon a simple single chamber design: • Central powder feed chute • Outward inflating packing head with powder recovery filter • Two-stage dust exhaust • Continuous liner cartridge. Four Hyperlon gauntlets were provided to permit operator access. This material was chosen for its resistance to cleaning solvents, and its proven resistance to molecular level migration into the glove that would otherwise create an operator safety risk. The continuous liner system (Fig. 5) permits the creation of a polyethylene liner bag from a stock of tubing held above the packing head. This technique allows powder from the IBC to flow directly into the liner bag, protecting the isolator interior from contamination. In-line powder sampling is provided by a CLS sampler unit mounted in the feed chute above the isolator housing. The sample collection pot was mounted inside the isolator, thus permitting contained sample recovery. A special 100mm sample bag out-port on the right hand side of the isolator permits removal of the 60cc sample from the isolator, without breaching containment. The weigh platform for the drum in the base of the isolator has a roller conveyor deck (Fig. 6) with a fold-down roller track extension (Fig. 7) located behind the swing-open drum entry/exit door. Due to the complexities of nitrogen purge and the CIP system, a housing on the left hand side of the isolator was developed to conceal valves and pipelines and to provide a local operator control panel. Filtration of the high-potency dust collected was effected by safe change "bag in/bag out" disposable filters – F9 fine dust filter with H13 HEPA filter. The safe change housings were specially developed by CLS for this project, having "Gold Seal" deep groove bag-attachment spigots and heavy-duty gas-tight doors to ensure that stringent leak-proof standards of the Helium Leak Test would be met. Fig. 8 shows the location of dust sampling equipment. The isolator area was in a positive pressure environment and as shown in Table 1, the drum swabs produced results below 1µg. Table 2 shows the IOM head samples produced results below 1µg on RUN 1, and part of RUN 4. Higher results during the tests were caused by leakage from the test set-up feed chute and not by operator error or isolator failure. The critical objectives for the client with this contained pack-off system were the assurance of operator safety and effective cleaning ability, while providing a high throughput powder pack-off system. The results received at the Factory Acceptance Test (FAT) are shown in Table 3. This project reflects the resources and analytical ability of CLS to meet very high levels of operator protection, while ensuring production efficiency and ease of clean down are not jeopardised. The FAT provides the ideal platform for testing adjustment, re-testing where necessary and finally for full client approval of all of the key parameters. Neil Cocker, manager of CLS's High Containment Group, summed up the intensive activity during the FAT: "Many isolator builders can provide well-made housings and even good ergonomic designs. However, the challenge here was to demonstrate that the total package of isolator, continuous liner, product sampler and the CIP system, would all deliver safe performance when tested under simulated operating conditions. Not many vendors can provide such a dedicated service."