Hans Schlatter, of Swiss firm Siegfried, highlights critical steps in API manufacture through a look at the company's recently opened facility in Zofingen
To ensure that tablets and capsules are produced to a reproducible standard, the active ingredients must always exhibit the same characteristics. This means they must have a consistent particle size and homogeneity, irrespective of the amount supplied. To satisfy this requirement, in 2004 Siegfried commissioned a new milling and blending facility for active pharmaceutical ingredients (APIs) at its headquarters in Zofingen, Switzerland.
Milling and blending processes require the observance of high safety standards and quality guidelines. Both the safety of the personnel and the protection of the substances from contamination play an important role. The facility must be flexible in its operation and also able to be cleaned quickly and effectively, especially since the product manufactured may change from one day to the next. Siegfried's new building aims to fulfil all these requirements.
The two installations were built as closed systems, preventing product fines from escaping into the surrounding environment as well as avoiding a contamination of the product with foreign particles.
The individual units, such as the charge unit, doser, mill, blender and discharge/filling station are located on four different levels within the building, using gravity to aid material flow.
Two trains, each with a different capacity and separated from each other, allow the handling of very fine products, or products with higher density and poorer flow properties. Different mills and sieves can be inserted into the train.
minimal contamination
Instruments such as the drum tilting/docking device and low-contamination split valves with built-in dust extractors for charging the desiccated agent from 200 litre bulk containers or filling the milled product into packaging, enable operation of the facility with minimal dust contamination. Throughout the entire process, the APIs stay within a closed system. Samples can be automatically taken from predetermined points after the milling and during the final packaging, without endangering the product or the employees.
Filling of the delivery packaging occurs with a continuous inliner bag which is locked with a clip closure, filled, locked again with a clip and then separated with a knife. Critical processes such as charging, milling and filling are carried out in a controlled environment under defined conditions with respect to air pressure, temperature and humidity. Access to these rooms occurs via separated personnel and material airlocks, with clear hygiene and dress codes for the employees.
inert atmosphere
The facility is washed down with a cleaning-in-place (CIP) system. Fast-running mills and airborne fine powder make a potentially explosive combination. For this reason, it was decided that the entire system should be operated under an inert (nitrogen) atmosphere. The oxygen concentration is always kept to below 6%. A positive result of a nitrogen atmosphere is the increased safety for the product as regards decomposition. To further minimise the risk of a dust explosion or the consequences of an extravasation (leakage) of fluid during the cleaning, all electrical installations incorporate extensive anti-explosion protection technology (EX standards) and follow ATEX Directives.
Both installations were inspected by the US Food and Drug Administration (FDA) and the Regional Health Inspectorate in 2006, and were given an NAI (no action indicated) assessment.
Both milling and blending installations are automated to ensure an efficient and reproducible processing. Certain components (e.g., mixing containers or part of the filling and discharging systems) are equipped with their own Siemens S7-300 PLC controllers. A server with two workstations sets up and supervises the milling processes, ensures a constant visualisation of the ventilation data, and if necessary, sounds an alarm, displays the line operation using WinCC and maintains a short-term operational data archive. A long-term archiving system that tracks several locations will be introduced during the course of the year.
In order to house the facilities for the two milling lines, a new 25m-high building was erected using reinforced concrete. Large window fronts in the manufacturing rooms promote transparency and provide a pleasant working environment for the employees. The internal configuration of the building was drafted and constructed so that all cGMP requirements could be satisfied.
The manufacturing rooms and airlocks were constructed using the latest technology: The cleanroom walls are made of anodized aluminium and the double ceilings with integrated lighting perfectly segregate the technical infrastructure, energy sources and all air supplies. The large capacity air conditioning system guarantees that all rooms maintain a constant temperature between 21° and 26°C and at a humidity of between 40% and 60%.